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A comprehensive textbook on medicated chewing gums

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 Book Contents
Chapter No. Table of Contents Page No.
1. Medicated Chewing gums- An Introduction 1-13
Prerna Kaushik , Pankaj Kumar, Deepak Kaushik*
2. Formulation & Manufacturing Methods of Medicated Chewing Gum 14-28
Prerna Kaushik , Pankaj Kumar, Ravinder Verma , Deepak
Kaushik*,
3. Aspects of Taste Masking in Medicated Chewing Gums 29-50
Prerna Kaushik , Vandana Singh, Vineet Mittal , Deepak Kaushik*
4. Medicated Chewing Gum- Patents & Recent Applications 51-60
Prerna Kaushik, Md. Habibur Rahman, Deepak Kaushik*
5. Patented Technology Platforms for Medicated Chewing Gum 61-68
Deepak Kaushik*, Prerna Kaushik, Pankaj Kumar
6. Evaluation of Medicated Chewing Gums 69-76
Prerna Kaushik, Deepika Purohit, Ravinder Verma ,Deepak
Kaushik*
7. Packaging & Regulatory Aspects of Medicated Chewing Gums 77-84
Prerna Kaushik, Ritu Kaushik, Parijat Pandey, Deepak Kaushik*
8. Conclusion 85

*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, India

Tel: +9315809626; E-mail: deepkaushik@rediffmail.com

i
ii
 CHAPTER 1
MEDICATED CHEWING GUMS- AN INTRODUCTION
Prerna Kaushik1, Pankaj Kumar2, Deepak Kaushik1*
1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana),
India-124001
2Wipro Pvt. Ltd, Sarita Vihar, New Delhi, India-110044

1. INTRODUCTION
The drug administration by oral route affords numerous benefits like the comfort of
administration, precise dosage, self-medication, and patient conformity (Lachman and
Lieberman, 2013). The key types of oral formulations are syrups, solutions, elixirs, suspensions,
emulsion, powders, tablets, and capsules, etc. Drugs nasty taste and poor palatability are the
ultimate difficulties in administering oral dosage form to children, as indicated by more than
90% of pediatricians in the U.S. (Kaushik and Dureja, 2014). Due to limitations of these oral
dosage forms, taste-masked medicated chewing gums soon became friendly to people because of
their convenient administration. Further, it delivers proven health, nutrition, cognitive benefits,
amusing taste, and good feeling. Medicated chewing gum act as an extended-release formulation
that delivers a constant release of medicament contained. This elegant, non-invasive drug
delivery system could be a boon in treating localized oral disease. Medicated chewing gums are
well-defined by the European Pharmacopoeia in 1991 by the Committee for Medicinal Products
for Human Use (CPMP) as “a gum base preparation meant to be chewed, providing a deliberate
and extended-release of the active constituent contained" (European Pharmacopoiea, 2009).
The triumph of nicotine chewing gum in the 1980s has led to more gratitude for chewing gum as
a drug delivery system. Medicated Chewing gum has been exploited for various medications
such as Cetirizine, Dextromethorphan Hydrobromide, Dimenhydrinate hydrochloride, Nicotine,
Antacids, Miconazole, Aspirin, Caffeine, Antimicrobial decapeptide, Ondansetron
Hydrochloride, and Nystatin etc. Medicated chewing gum provides both local as well as
systemic benefits after permeation through the buccal mucosal or from the GIT. Chewing gum is
readily absorbed across oral mucosa and provides a fast systemic effect. The medication's
physiochemical characteristics like aqueous solubility, pKa value, the partition between
gum/saliva, munching time, chewing frequency, impact the release of drugs from the gum (Asija

1
et al,. 2012). The researchers perceive medicated chewing gum as a commercial and possible
drug delivery system as it is suitable and can be taken discreetly without water. Nowadays,
enriched technology and skills have made it conceivable for the researchers to evolve medicated-
chewing gum with pre-set properties. Treatment of fungal diseases, caries prevention, smoking
termination, ever-lasting flavored, biodegradable gums, sustained-release gums are some of the
popular applications to be comprehended in the future (Lee et al., 2001). This chapter focuses on
different aspects of the oral route and a brief introduction to medicated chewing gum.
1.1 ORAL DRUG DELIVERY ROUTE
One key restraint of the oral route is the influence of first-pass metabolism and pre-systemic
deterioration. The amount of the drug can be augmented to confirm bioavailability after
absorption. This augments the possible side effects and over-dosing of the drug. The prospect of
evolving an appropriate oral delivery system, which can bypass the first-pass metabolism, is
perhaps possible by using chewing gums (Surana, 2010).
1.1.1 Drug absorption through Buccal mucosa (Rathbone et al., 1996)
The oral mucosa provides a route for the absorption of suitable drugs and a hurdle to secure the
body from harmful substances. The mouth and cheeks are bordered with a permeable epithelial
layer, which delivers a speedy absorption due to its profuse vascularity. The absorption of the
drug across the oral mucosa circumvents the first-pass metabolism or related enzymatic
deterioration. This bids chance for drugs that are mainly vulnerable to the acidic conditions
inside the gastrointestinal tract (GIT). This augmented bioavailability results in a lesser adjusted
dose, which results in fewer gastric side effects (Conway, 2007). The oral epithelium, lamina
propria, and submucosa are the three main layers of the oral mucosa, which are shown in Figure
1.1 (Shinkar et. al., 2012). Various features of oral epithelium drug delivery are depicted in
Figure 1.2. The epithelium of the mouth may be non-keratinized or keratinized. The epithelium
with the keratin layer is dry, hard, and chemically impervious, which is found in the gingival
mucosa and hard palate of the oral mucosa. The non-keratinized epithelium is comparatively
flexible and is found in the soft palate of the mouth, cheeks, and lips. There is a basement
membrane that separates the oral cavity epithelium from the underlying connective tissue. The
lamina propria covers a sheet of connective tissue holding elastic collagen fiber. It also contains
blood vessels and nerve filaments through which the drug actives can enter the systemic
circulation (Rathbone et al., 1996; Squier et al., 1996).

2
.

Figure 1.1 Cross-section of the oral mucosa

Saliva is a hypotonic fluid containing an adjustable quantity of enzyme, mucus, antibodies, and
inorganic ions. The surface of the mucus layer is continually splashed by a salivary flow of
around 0.4 to 2L. The sub-maxillary, the parotid, and the sublingual are the three pairs of glands
that provide the primary salivary secretion. The existence of saliva in the mouth is imperative as
drug permeation through damp membranes occurs much more promptly (Squier et al., 1996).
Medicated chewing gum also gains entry into the systemic circulation after dissolving in the
saliva.
1.1.2 Mechanism of drug transport (Pagare et al., 2012)
Amidst chewing, the drug enclosed within the formulation is liberated into the saliva and is
either soaked through oral mucosa or through GIT. The drug delivery through buccal mucosa
obeys simple passive diffusion. Some carrier-mediated transport is also observed. The drug flux
may be enhanced by reducing the diffusional barrier of the membrane by providing it more
fluidity, enhancing the drug solubility in the saliva, or improving the lipophilicity of the drug
using various techniques. The drug permeates through the buccal mucosa via two pathways i.e.,
transcellular and paracellular. The mechanism of drug movement across the oral epithelium may
be explored via numerous techniques like microscopic techniques using autoradiography,
fluorescent dyes and confocal laser scanning microscopic procedures, etc.

3
 • Provides a moist and stable environment
• Enhances the dissolution
Saliva • Salivary acidic pH favors absorption for
wide range of drugs

Oral structures • Offer a variety of sites for drug delivery

• Provides chewing, absorption etc.
(Teeth, membranes, • Exposes new surfaces for drug release
tongue)

• Thin mucosa provides rapid absorption

Membrane • Offers wide surface area for drug
absorption
Properties

Figure 1.2 Various aspects of oral mucosa for chewing gum delivery
1.2. MEDICATED CHEWING GUM
Medicated Chewing Gum (MCG) is a unique, elegant, and patient-friendly drug delivery system
comprising a masticatory gum base with the pharmacologically active ingredient. The concept of
the Elegant Drug Delivery System (EDDS) provides the administration of drugs or a
combination of drugs in an innovative and attractive manner (Biswal and Anantkumar, 2013).
Chewing gum has been utilized to convey medicinal actives such as nicotine for smoking
termination. The ancient Greeks used to chew gum-like substance from archaeological digs of a
tree found in Finland and Sweden (Rassing, 1996). The first marketing of chewing gums was in
1848 when John Curtis and his son sapped chicle from the Sapodilla tree. In 1869, Doctor
William F. Semple from Ohio issued the first patent for chewing gum comprising licorice and
rubber dissolved in alcohol and naphtha to protect teeth. In 1892, Wrigley introduced its primary
chewing gum products, Vassar & Lotta (Shah& Mehta 2014). Chewing gum stimulates saliva,
which contains antibacterial agents and is a potent guard of the oral cavity. Saliva has various
protective (anti-caries) roles as it swipes away food debris and the bicarbonate and calcium ions
nullify plaque acid related to dental caries. Saliva (Jacobsen et al., 2004). The benefits of

4
medicated chewing gum are numerous, which have been described in Figure 1.3. (Mehta et al.,
2010; Heema and Stuti, 2010).

Taken
without
water
Reduce risk Local as well
of gastric as systemic
intolerance effect

Fast onset Valuable in

of action dysphagia

Avoids first Good for

pass Children & old
metabolism patients

Figure 1.3 Advantages of Medicated Chewing gums

The released drugs from chewing gum will be accessible in a readily bioavailable form, thus
providing fast release. The treatment can be dismissed at any time by throwing the cud after
chewing. Medicated chewing gums possess certain demerits also (Morjaria et al., 2004, Weil et
al., 1978). A chewing gum containing sorbitol may cause flatulence, diarrhea. Condiments in
gum like cinnamon and licorice may cause various allergic reactions, ulcers, and hypertension.
Chlorhexidine has limited application for oromucosal delivery because of its nasty taste and teeth
discoloration property. Chewing gum can stick to the teeth enamel, and continuous chewing may
cause pain in facial muscles. Chewing can produce a constant stream of saliva, a waste of
resources that could be utilized for some other vital metabolic actions. Mostly chewing gums are
sugared with aspartame that may cause diabetes, cancer, neurological disorder, and natal defects.
1.3 DRUG RELEASE MECHANISM FROM CHEWING GUMS
The masticatory action on chewing gum exposes new surfaces for the interaction between gum
and saliva. Saliva diffuses through the gum's hydrophilic components and partitions out the drug
entering the oral cavity. The European Pharmacopoeia official masticator reproduces these

5
conditions in vitro. As the drug is dissolved into saliva, it is bioavailable for local as well as a
systemic effect through the jugular veins, decreasing the lag phase for onset. Aspirin, Caffeine,
and Dimenhydrinate showed a faster absorption from chewing gums as compared to standard
tablets (Khatun and Sutradhar, 2012). After reaching the circulation, the active can be
conveyed to the required site of action (Chaudhary and Shahiwala, 2010). A concentration
difference must be preserved in the buccal cavity for a while to boost absorption through passive
diffusion. The disparities in therapeutic efficacy from medicated chewing gums can be attributed
to different chewing styles, chewing frequency, intensity, swallowing disparities, saliva
production, etc. These disparities can be minimized by proper patient training in order to
maximize drug release and subsequent absorption. The mean chewing time for studying in vitro
release from chewing gums has been publicized as 30 minutes, and the average chew rate is 60
chews/ minute (Barabolak et al., 1991). The drug release factors & mechanism is depicted in
Figure 1.4 (Paul & Behl 2015).
1.3.1. Mucosal drug delivery considerations (Rindum et al., 1993; Rowe et al., 2003)
Various factors regulate the mucosal drug delivery, which comprises membrane factor,
environmental factor, and formulation factor. The amount and the degree of drug reaching the
systemic circulation are affected by a change in permeability and thickness across the oral
mucosa. The drug transfer is affected by the composition and keratinization of the mucosal
membrane. Other factors such as blood/lymph drainage, cell renewal rate, membrane thickness,
blood perfusion rate, and enzymes control the amount and the degree of drug absorption. Saliva
contributes to an environmental factor. It comprises of 99% water and has a pH of 6.5 to 7.5
depending on the site and rate of flow. Enhanced salivary secretion influences the membrane
thickness and helps in the easy passage of the drugs.

6
 • Lipophilic component of the gum plays important role
Formulation

• Saliva diffuses into gum and drug distributes into saliva

Mastication • Solubility determined approach

• Drug in saliva partitions into buccal membrane

Permeability • Lipophilicity dependent approach

• Drug moves through buccal membrane

Passive • Depends on concentration gradient
diffusion

• Drug moves from systemic circulation to the site of action

Absorption

Figure 1.4 Process of in vivo drug movement from chewing gum

The pH of the salivary fluid is also vital for the passive distribution of the unionized drug.
Chewing time should be around 20 to 30 minutes, and the average chewing rate is about 60
chews/min. Drugs with the water solubility between 1:10 and 1:300 show up to 60% release
within minutes of chewing and 70%-90% when the gum is chewed for 15 minutes. The less
water-soluble drug will be released slowly. The drug's physicochemical characteristics play a
very imperative aspect in the release of the drug from chewing gum. The drug which is soluble in
saliva will be released instantly while lipophilic drugs are released gradually (European
Pharmacopoeia Directorate, 2000). The formulation factor also plays a major role as the
quantity of gum base impacts the active ingredient's release rate. If the gum contains more
lipophilic part, the drug release rate is decreased (Naik et al., 2010).
1.4 APPLICATIONS OF MEDICATED CHEWING GUMS
The medicated chewing gum has gained increasing recognition as a drug delivery system for
various applications, such as preventing dental caries, smoking termination, analgesic, obesity,
xerostomia relief, headaches, minor pains, and muscular aches, etc. (Table 1.1). It also re-boost
the pH of the plaque, which lowers the severity of dental caries. Caffeine, Chromium, and
Guarana are shown to be competent in preventing obesity (Pittler et al., 2003). The future of the

7
chewing gum seems to be brighter than ever. Various commercially available medicated chewing
gums have been tabulated in Table 1.2 (Shah& Mehta, 2014, (https://www.pr.com/press-
release/39659).
Table 1.1 Formulated medicated chewing gums
Drug/active ingredient(s) Indication(s) Reference
Aloe vera Oral wound healing, antibacterial Aslani et al., 2015
Caffeine Alertness Aslani& Jalilian, 2013
Cetrizine Common cold Chaudhary&Shahiwala, 2012
Dextromethorphan HBr Antitussive Swami et al., 2012
Diltiazem Angina Pectoris Pandit & Joshi, 2005
Dimenhydrinate HCl Nausea Mehta and Trivedi, 2011
Dolasetron Antiemetic Shaikh et al., 2017
Domperidone Maleate Antiemetic Paradkar et al., 2016
Famotidine Antacids Mehmood et al., 2014
Ginger Antioxidant Aslani et al., 2016
Guaiefenesin Cough Dabhi & Jeevani, 2019
Indomethacin Analgesic Chandran et al., 2016
Lymecycline Antibacterial Jeyapriya, 2018
Metformin Antidiabetic Mostafavi et al., 2014
Nicorandil Cardiovascular Diseases Yashaswini et al., 2010
Nicotine Smoking Cessation Aslani & Rafei, 2012
Promethazine HCl Motion Sickness Rao et al., 2011
Simvastatin Antihyperlipidemic Vijay et al., 2016

Table 1.2. Widely used medicated chewing gums throughout the world
Trade Mark Active Substance Aim Commercially
Available
Aspergum Aspirin Pain relief North America
Nicorette Nicotine Smoking Termination Worldwide
Nicotinelle Nicotine Smoking Termination Australia,
Western

8
 Europe,
Superpep Dimenhydrinate Motion sickness Germany,
Switzerland
Chooz Calcium Carbonate Antacids USA
Brain DHA & CCE Cognition Enhancer Japan
Stay Alert Caffeine Alertness USA
Buzz Gum Guarana Alertness United
Kingdom
Travvel Dimenhydrinate Motion USA, Australia
sickness
V6 Xylitol Dental caries United
Kingdom
Orbit white Calcium as tricalcium phosphate Dental hygiene India

Zoft stress gum Extracts of Passion Flower, jujube Reduces stress, USA
Fruit, Ashwagandha, and Calcium anxiety, and
carbonate depression
Zoft virility gum Extracts of Horny Goat Weed, Upsurges male sexual USA
Hawthorn Berry, etc. desire

Zoft Breast gum Fenugreek seed extract, fennel seed, Enhancement of breast USA
etc.
Zoft Menopause Dong Quai root, Black cohosh root Reduces the symptoms USA
gum extract associated with
menopause

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13
 CHAPTER 2
FORMULATION AND MANUFACTURING METHODS
Prerna Kaushik1, Pankaj Kumar2, Ravinder Verma 1, Deepak Kaushik1*
1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana),
India-124001
2Wipro Pvt. Ltd, Sarita Vihar, New Delhi, India-110044

2. INTRODUCTION
Chewing gum as a drug transport system can be used for various local and systemic diseases by
altering the formulation and industrial parameters. Medicated chewing gum is a blend of natural
or artificial resins sapped from trees that contain active ingredients, sweeteners, coloring, and
flavoring agents. Gum bases are commonly lipophilic and generally present between 40 – 70 %
of the whole gum formulation (Lee, 2001). The chewing gum composition is critical, which
affects the characteristic masticatory texture and feel of the product. Cyclodextrin complexation,
ion exchange resins, solubilizing agents, and buffering agents are some of the formulation
techniques that may alter the drug's aqueous solubility and release profile. There is a requirement
to revitalize current drugs into novel drug delivery systems (NDDS) to encompass or defend
product patents, thus circumventing generic erosion at patent termination. MedChew®
technology of Fertin Pharma is drawing attention from numerous prime pharmaceutical players.
Its most innovative teamwork is the Met-Control project with U.S. venture Generex
Biotechnology to develop a chewing gum containing metformin for diabetes treatment. One
another landmark is its collaboration with companion syndicates Novartis and GSK for the
production of gum bases, Nicotinell®, and Niquitin® chewing gums (Fertin Pharma, 2003).
The medicated chewing gums are prepared using conventional melting, cooling-grinding, and
directly compressible methods. The chapter debates about the composition, formulation aspects,
and development methods of medicated chewing gums.
2.1 COMPOSITION OF MEDICATED CHEWING GUM
Chewing gum is a blend of various natural or artificial excipients, which are described in Table
1 (Patel et al., 1990, Gadhavi et al., 2011, Gavaskar et al., 2011). The vital excipient for
chewing gum is natural gum, Chicle, which is botanically known as Manilkara zapota and
obtained from the sapodilla tree. This artifact is harvested during the damp condition from July

14
to February (Conway et al., 2003; Zyck et al., 2003). Chemically, Chicle is composed of
polyterpenes that contain numerous isoprene units. It is very costly and hard to obtain so other
natural gums or man-made polymers like polyvinyl acetate, butadiene-styrene copolymers can be
used as a gum base. The chewing gum contains two portions, one is a water-insoluble gum base
portion (Elastomers, plasticizers or fillers), and the other is a water-soluble bulk portion (active
constituents, sweeteners, flavors, anti-tack agents) (Nagaswami et al., 2004).
2.1.1 Elastomer, plasticizers or fillers
Elastomer delivers flexibility and maintains the gluey texture. Natural rubbers or gums like
Chicle, Lechi Caspi, Jelutong, and Perillo may be used (Asija et al., 2012). Vijay et al., (2016)
formulated an antihyperlipidemic chewing gum of Simvastatin by extracting Chicle from the
Sapodilla tree. The gum base was converted into a directly compressible gum base powder in
which Talc was added as filler. Shete et al., (2015) formulated a medicated chewing gum to
avert motion illness by extracting a natural gum base, Prolamin, from wheat. The chewing gum
exhibited good elasticity and high water retention capability. The artificial gum base includes
various polymers like polyvinyl acetate, polyvinyl–alcohol, polyisobutylene based on the
molecular mass, and consistency looked-for. They decrease the affinity of the gum to stick to the
teeth (detackifier). The gum base regulates the formulation's critical features such as elasticity,
fragility, texture, smoothness, hardness, tackiness, and mouthfeel. It also governs the release
pattern of drugs and flavors. The formulation procedure can be boosted by using a directly
compressible chewing gum elastomer (Gadhavi et al., 2011). Gums formed using directly
compressible powder are analogous to tablet in appearance and are easy to manufacture. Various
directly compressible elastomer powders are Pharmagum M®, Health in Gum®, Chewmed®,
Rev-7® etc. In a study, the Nicorandil chewing gums were prepared using different ratios of
directly compressible elastomer (Pharmagum-M) to treat cardiovascular diseases (Yashaswini et
al., 2010). Plasticizers are used to control the gumminess of the product and are classified into
natural and artificial. It includes glycerol esters, hydrogenated rosins, terpene resins, α-pinene, d-
limonene, etc. In work by Pandit and Joshi (2005), ester derivatives of rosin (hydrophobic gum
base) were used as a base for the formulation of Diltiazem chewing gum to prevent angina.
Softeners improve the chewability and mouth feel of the gum. They include Glycerin, Lecithin,
Tallow, Hydrogenated Tallow, Mono/ di/ tri-Glycerides, Stearic acid, Palmitic acid, Oleic acid,
Linoleic acid, etc. Rajitha et.al, (2016) formulated and evaluated a patient-friendly medicated

15
chewing gum of Chlorpheniramine Maleate in order to enhance drug release. The melting
method was used to prepare the gums in which altered gum base concentrations and plasticizers
like glycerol and castor oil were used.
2.1.2 Fillers/Texturizers
They control chewability and impart texture. Magnesium carbonate, alumina, aluminum silicate,
calcium carbonate, limestone, magnesium, clay, talc, titanium oxide, Mono/ di/ tri calcium
phosphate are some of the commonly used fillers (Bumrela et al., 2005).
2.1.3 Colorants and whiteners
They include various types of colorants, lakes, fruit-vegetable extracts, Titanium Dioxide, etc.
The US FDA has permitted artificial colors for use in drugs, foods, and cosmetics, whereas, in
the European Union, both artificial and natural colorants are acceptable in the food industry. The
subsequent seven coal tar dyes are permitted for food and drug applications in the U.S., as
described in Figure 2.1. (Chaudhary and Shahiwala, 2010).

FD&C Blue
No. 2 --
Indigotine,
E132 (dark
blue shade)
FD&C Blue FD&C Green
No. 1 -- No.3 -Fast
Brilliant Blue Green FCF,
FCF, E133 E143 (bluish-
(blue) green)

FD&C Red No.

40 - Allura Red
AC, E129 (red)
FD&C Yellow
FD&C Red
No. 6 --
No. 3 -- Sunset Yellow
Erythrosine, FCF, E110
E127 (pink)
(orange).

FD&C Yellow
No. 5 --
Tartrazine,
E102 (yellow)

Figure 2. 1 Colorants approved for food applications

But as most of the colorants causes rashes and aggravates allergic reactions, pharmaceutical
companies are more inclined towards natural pigments obtained from herbal and animal sources.
Plant essences such as Curcumin-yellow, Annatto-yellow, Chlorophyll-green, Saffron yellow,
and animal excerpts like Cochineal red are used for pleasing appearances. Titanium dioxide and

16
magnesium oxide are also incorporated to provide opaqueness to the final formulation (Sameja
et al., 2011).
2.1.4 Sweeteners
Sweeteners provide the taste masking for the bitter actives present in the gum and can be used as
softeners to mix the constituents and preserve moisture. These include dextrose, maltose, dextrin
Sorbitol, Starch hydrolysates, xylitol, sucrose, fructose, galactose, corn syrup etc. Corn syrup
provides the freshness & flexibility to the gum. High-potency synthetic sweeteners such as
Sucralose, Aspartame-Acesulfame salt, Alitame, Saccharin, Glycyrrhizin, Dihydrochalcones, etc.
can also be incorporated to deliver enduring sweetness and flavor sensitivity (Sharma et al.,
2013). Caffeine gum was prepared Aslani& Jalilian, 2013 to decrease the unpleasant taste of
caffeine. Various sweeteners like sorbitol, mannitol, aspartame, liquid glucose, xylitol were used.
The caffeine release from the gum base was examined by the in-vitro chewing gum apparatus,
and a content uniformity test was also done on the chewing gums.
2.1.5 Flavoring agents
Various natural and artificial flavoring agents used to improve aroma include essential oils such
as Spearmint oil, Mint oil, Clove oil, ginger oil, Citrus oil, fruit essences, and Peppermint oil,
Oil of Wintergreen, etc. The Nicotine gum was formulated by (Aslani & Rafei, 2012) using the
gum bases, a sweetener like stevia, licorice, aspartame, a taste-masking component like zinc
acetate, or sodium chloride, and a flavoring agent like cherry, peppermint, etc. All the
preparations were examined for the impact of various flavors on masking Nicotine's unpleasant
taste (Bindi et al., 2011).
2.1.6 Active component
The percentage of an active pharmacological agent may vary from 0.5-30% of the final gum
mass. A lipophilic, enzymatically stable, small size unionized active component is anticipated to
penetrate more readily from the buccal membrane (Pagare et al., 2012). A saliva soluble
component is liberated in less than 10-15 minutes of chewing, whereas the lipophilic component
will be absorbed slowly. The core consists of an insoluble gum base that can be coated with
sweeteners, flavors, polymers, actives, colors, etc. Molecular weight below 100 daltons is
quickly conveyed through buccal mucosa (Runwal et al., 2008). To optimize the absorption rate,
a drug should be present in the salivary layer at its maximum solubility. Table 2.1 shows various
excipients used in the manufacturing of medicated chewing gum. Various actives such as

17
Econazole, Silver acetate, Cetrizine, Nystatin, Dextromethorphan HBr, Miconazole, Nicotine,
Aspirin, Methadone, Caffeine, Chlorhexidine, Dimenhydrinate may be incorporated (Swami et
al., 2012).
Table 2.1 Excipients used in medicated chewing gum
Category General Examples
range
Active 50% Aspirin, Nicotine, Dextromethorphan Hydrobromide, Caffeine,
substances Miconazole, Domperidone, Ginger, Vitamin C, Green Tea
Elastomers 15-45% Natural - nispero, Chicle, crown gum,
Synthetic- polyisobutylene, butadiene-styrene copolymers, isobutylene
isoprene copolymers
Elastomers 45-70% Natural rosin esters, terpenes, d-limonene, a-pinene, b-pinene
solvents
Softeners 0.5-15% Glycerin, fatty acids such as palmitic acid, stearic acid, oleic acid, and
linoleic acid, and lecithin
Sweeteners 40%-50% Water-soluble sweetening agents -xylose, glucose, galactose, sucrose,
fructose, maltose,
Sugar alcohols-sorbitol, xylitol
water-soluble artificial sweeteners- saccharin salts, cyclamate salts
dipeptide based sweeteners -aspartame, alitame
protein-based sweeteners -thaumatin I and II
Flavoring 0.01% Peppermint oil, anise oil, ginger oil, banana, spearmint oil, pineapple etc.
agents
Colorants 0.1% Various colors approved by F.D. &C
Opacifiers 0.5-2% Magnesium oxide, Titanium dioxide
Texturizing 50% Bentonite, Talc, calcium carbonate, tricalcium phosphate, magnesium
Agents carbonate, magnesium aluminium silicate
Antioxidants 0.02% Propyl gallate, butylated hydroxyanisole (BHA), and butylated
hydroxytoluene (BHT)

18
2.2 FORMULATION DEVELOPMENT – CONCEPT

A chewing gum formulation is a complex approach. If a gum base contains a high amount of
softeners and emulsifiers, it increases the release of actives, while hard gum may delay the
release. The amount of water in chewing gum is very little hence no preservative is required. The
gum base regulates the product's vital features, e.g., the texture, gumminess, crumbles. The
medicated chewing gum can be modified for both increased and sustained release. Cyclodextrin
complexation, microencapsulation, or other solubilization technique enhances the aqueous
solubility, stability, taste, and bioavailability of a diversity of active ingredients in formulations
(Pedersen et al., 1990; Rindum et al., 1993, Abelson et al., 1990; Christrup et al., 1990).
Various concepts of formulation development are discussed below:
2.2.1 Cyclodextrin complexation
Cyclodextrins are primarily oligosaccharide particles having an annular shape, with a
hydrophobic inner pocket and a hydrophilic outer surface. This configuration permits
cyclodextrins to enclose aptly sized non-polar guest molecules inside the hydrophobic central
pocket, to form clathrates. As the periphery of cyclodextrin is hydrophilic, the formation of such
complexes may be used to enhance the solubility of less soluble drugs. The α, β, and γ types are
naturally occurring cyclodextrins comprising six, seven, and eight glucopyranose units,
respectively (Haghbani &Nazzal, 2018, Pagare et al., 2012). Hydrophilic cyclodextrin, such as
2-hydroxypropyl β-cyclodextrin (HPbCD), is considered harmless at low concentrations, and it is
used to enhance the water solubility of poorly water-soluble drugs (Kasa et al., 2013). But due to
the potential toxicity of lipophilic cyclodextrin byproducts, their oral administration is limited.
The drug- cyclodextrin complexation is shown in Figure 2.2.

Figure 2.2. Formation of drug-Cyclodextrin complex

19
Chaudhary& Shahiwala, (2012) focussed on the taste masking of Cetrizine by cyclodextrin
complexes, its preparation in the form of medicated chewing gum, and it's evaluation with the
study of possible factors impacting drug release by factorial designs.
2.2.2 Microencapsulation
Microencapsulation by using polymers is one of the fruitful techniques for sustaining the release
of actives, sweetener or flavors from medicated chewing gum. The fast depletion of the flavor
and sweetness perception throughout chewing is a common problem. The particle size of the
active component also plays an important role (Pagare et al., 2012). To circumvent
disagreeable grainy feelings during chewing or the risk of harming the teeth' enamel, the
particle size should be kept less than 100 μm. Both of these problems can be solved by
microencapsulation. Yang et al. (1988) patented an encapsulation preparation containing a
polyvinyl acetate film, a hydrophobic plasticizer, and aspartame prepared by melt blending and
embodied inside chewing gum for controlled release of the active agent.
2.2.3 Increased release
Most of the drugs are lipophilic, and thus only a small portion of the drug incorporated is
released despite continuous chewing. For such drugs, various rectifications like the use of
buffering agents, solid dispersions are needed. Folic acid is useful for gingivitis. In a study, the
chewing gum formulations of folic acid containing various buffering agents like sodium
bicarbonate and sodium carbonate have been prepared. Both in vivo and in vitro activity were
carried out, and it was found that the release of drug is higher in the formulation with buffers
than the one that did not contain any buffering agent. Nystatin, antifungal medication, was
coated using hydrophilic Arabic gum. It was noticed that the drug release increases as the
uncoated drug is converted into the coated one. Moreover, the effect of various solubilizing
agents such as Tween 60, Panadan AB 90 and Cremophor RH40 has been studied on Nystatin.
The drug release was noted to increase. In contrast, contrary results were observed through the
study of Propanolol HCl and Metronidazole with glycerol and span 20 (Abelson et al., 1990).
2.2.4 Sustained release of the drug
The binding of lipophilic drugs to ion exchange resins delivers sustained release. Also, this
approach is useful to mask the bitter taste of drugs. To mask the taste, weak cation exchange or
weak anion exchange resins are used, based on the drug type. The drug resin complex (resinate)
does not break at salivary pH of 6.7 and cation concentration of approx. 40 meq/l, but it is

20
dissociated by the acid present in the stomach (Guo et al., 2009). The resinate is tasteless but the
rationale of oral bioavailability from chewing gum is not resolved. The rapid release profile of
nicotine from the chewing gum is undesirable for clinical use as a smoking substitute. To
elucidate the uniform release Nicorette® chewing gum was developed, in which nicotine was
complexed to a cation exchange resin - polacrilex resin, Amberlite IRP 64. An effort has been
made to prepare taste-masked medicated chewing gums of Lornoxicam by ion exchange resin,
Kyron T-114. This taste-masked chewing gum was prepared using directly compressible gum
powder health in gum (http://shodhganga.inflibnet.ac.in/jspui/bitstream/ 10603/
121763/14/15_chapter%206.pdf ).
2.3 MANUFACTURING PROCESS
The medicated chewing gums are sequentially prepared by placing the excipients in a mixer.
Once the constituents have been systematically mixed, the gum mass is collected from the
mixer and molded into the required form, which is then coated. Different methods used for the
manufacturing of Chewing gum can be broadly classified as;
x Conventional/ Melting method
x Freezing, crushing, and tableting method.
x Direct compression method (Rassing &Jacobesen, 2003, Bahl, 2015)
2.3.1 Conventional/ traditional method
The gum base constituents are liquefied and put in a kettle mixer/Z-Blade Mixer (Figure 2.3) to
which active ingredients, sweeteners, flavors, and other excipients are mixed at a certain time .
The gum at that point is guided through rollers and transformed into a thin strip. Throughout this
procedure, sugar substitutes can be added to enhance the flavor. The gum is chilled for up to 48
hours and cut to the required size. This technique has various limits. This method is not suitable
for thermolabile drugs as the high temperature is used in melting. Expertise is not so flexible to
incorporate strict manufacturing settings essential for the production of medicinal products
(Athanikar et al., 2001). Chewing gum tablets are difficult to form because of moisture content
(2-8%). If such a composition is grounded, it would stick to the grinding machine and would be
difficult to compress. Chewing gums of Chlorhexidine and Chitosan were prepared by Lakshmi
et al. (2014) using various gum base proportions by hot-melt technique. Chandran et al., (2016)
developed the medicated chewing gum enclosing Indomethacin I.P. using the melting process

21
and exposed to various characterization studies. The sequential steps of conventional methods
are shown in Figure 2.4.

Figure 2.3 Mixing through (a) sigma blade mixer, (b) sigma or Z-form blade

Gum Base (Chicle) is

sapped from the
tree.

Strip is cooled and

Gum base is dried
cut into desired
using hot air
shape

The liquified mass

Gum base is mixed
moves through
with other liquified
rollers to form a
excipients in a mixer
thin strip

Figure 2.4 Conventional/traditional (melting) method

2.3.2 Cooling, grinding and tabletting method
This technique has been established with an effort to lessen the moisture content and assuage the
difficulties mentioned in the traditional melting method. The chewing gum formulation (base) is

22
chilled to become adequately brittle without adhesion to the grinding apparatus. Generally, the
temperature of the frozen mixture is around -15˚C or lesser. Among the several coolants, solid
carbon dioxide usage is favored as it sublimes readily and does not produce any residue that may
be potentially dangerous. The cooled composition is then grounded to obtain fine particles.
Instead, the stages of cooling the chewing gum composition can be pooled into one step by
contacting the crushing apparatus with coolant or by placing the grinding apparatus in a cooling
jacket of liquid nitrogen. Certain excipients are added to the chewing gum preparation, such as
an anti-caking agent and grinding agent, to accomplish the desired properties (Athanikar et al.,
2001; Mochizuki et al., 1976).
2.3.3 Use of anti-caking agent
Precipitated silicon dioxide prevents the chewing gum particles from clustering. It should be
mixed with chewing gum formulation before grinding.
2.3.4 Use of grinding agents
To avoid the gum from jamming the grinding apparatus, various aids such as alkaline earth metal
phosphate, alkaline metal phosphate, or maltodextrin can be used. The therapeutic and safety
aspects can be at risk as their remains may pose problems. Once the composition is crushed to a
powder, the coolant can be removed by evaporation. The powder can be mixed with other
ingredients such as lubricants, binders, coating agents, and sweeteners in a suitable mixer such as
a sigma mill or a high shear mixer. Alternatively, a Fluidized Bed Reactor (FBR) can be used,
preventing the agglomeration of particles. Then granules can be mixed with anti-adherents like
Talc and mixed in a V- type blender for further compression. Bateddi et al., (2010) patented a
procedure for the formulation of medicated chewing gums using a powdered based gum. The
powdered gum base was cooled at a temperature between -70 ̊ C and -50 ̊ C to overcome the
limitations associated with the conventional melting method.
2.3.5 Directly compressible chewing gum excipients
A directly compressible chewing gum excipient can hasten the chewing gum manufacturing
process. The use of these excipients can correct the restrictions of the above described methods.
PHARMAGUM® is one such compressed gum system developed by SPI Pharma. Pharmagum is
a mixture of sugar alcohols with a chewing gum base. It is accessible as a directly compressible
powder that can be compressed into a gum tablet using a traditional tablet machine, thus aiding
the speedy and economical development of a gum delivery system (Athanikar et al., 2001). It is

23
prepared under CGMP conditions to be considered "Generally regarded as safe" (GRAS).
Pharmagum® is available in three types, namely S, M, and C, based on the number of
constituents. Pharmagum® M has a 50% more gum base compared to Pharmagum®S.
Pharmagum®S is made up of gum base and sorbitol. Pharmagum®M contains gum base,
mannitol & Isomalt. Pharmagum® C contains least amount of gum base with or without sugar.
The nicotine release from gum formulations using Pharmagum displayed a quicker release rate.
The formulations made with these excipients are analogous to a tablet in appearance. These
directly compressible systems enable a quick and cost-effective formulation compared to
traditional melting methods (William and Millind, 2012).The chewing gum formulations of
dextromethorphan hydrobromide were made by Swamy et al., 2012 to overcome the first-pass
effect and for attaining faster systemic absorption. The drug was then converted into spray-dried
form and incorporated into the Pharmagum M base to enhance the taste and solubility. The
Health in Gum® powdered excipient by Cafosa is an inimitable, distinctive system that allows to
develop compressed chewing gums. It is a directly compressible gum powder that contains vital
ingredients ready to be mixed with the active ingredient. Paradkar et al., 2016 formulated a
directly compressible Medicated chewing gum of Domperidone Maleate using Health in Gum®
(gum base) with a better taste by using a blend of the sweeteners.
2.4 PROBLEMS ASSOCIATED WITH MANUFACTURING CHEWING GUMS
Lamination, capping, picking, and sticking are the difficulties found during the production of
chewing gum. In the conventional method, the excessive amount of moisture in the matrix may
cause a low viscosity, which lessens the compressive strength. It becomes difficult to maintain
the accuracy and uniformity of the drug by heating and melting method. It is tough to provide
hygienic conditions to make chewing gums. In the cooling-grinding method, the moisture
content of chewing gum may jam the machine's blades and punches. In the direct compressible
method, the discharge of final compressed product from the mixer is problematic and may stick
to punches. Developing a chewing gum with less calories has resulted in a gum piece with stiff
chew, poor texture, and a bad taste. Sugar plugs in the final product can cause an undesired
perception. Some constituents and active agents can irritate the mucosa. High temperature to
facilitate the mixture of gum base, leads to spoiling other ingredients. Water elimination from the
final formulation needs progressive techniques to evade the hardness of the gum (Heema and

24
Stuti, 2010). The limitations of conventional and freezing methods are tabulated in Table 2.2
(Khatun &Sutradhar, 2012).

Table 2.2 Limitations of Conventional and freezing method

Manufacturing method Limitation
Conventional/ traditional method x Manufacturing of thermolabile drugs become
difficult.
x Precise dosing is not possible;
x High moisture content.
Freezing, grinding and tableting x Sophisticated equipment is required;
method x Entails careful monitoring of humidity

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44. Yashaswini, P. M., Someshwara, B., Ranjit, K., Vinod, R., Suresh, K., Kumar, P. (2010).
Formulation and Evaluation of Nicorandil Chewing Gum. RJPDFT., 2(4).
45. Zyck, D.J., Greenberg, M.J., Barkalow, D.G., Marske, S.W., Schnell, P.G., Mazzone, P.
(2003). Method of making coated chewing gum products containing various antacids.
US6645535.

28
 CHAPTER 3
CONCEPTS OF TASTE MASKING IN MEDICATED CHEWING GUMS
Prerna Kaushik1, Vandana Singh1, Vineet Mittal1, Deepak Kaushik1*,
1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak
(Haryana), India-124001

3. INTRODUCTION
Many drugs are too bitter or have other aversive attributes, making the formulation of palatable
drug products like medicated chewing gum a daunting challenge. Besides, sensory science and
the formulation principles associated with flavor building are not well established within the
pharmaceutical industry, which can obstruct the development of palatable drug products. This
leads to poor patient compliance. However, when compliance suffers, so do health outcomes.
The oral route of drug administration is a generally known technique of administering drugs
because of its numerous advantages (Lachman and Lieberman, 2013). The researchers' key
focus is to flourish formulations for oral use as they can be self-dispensed by the patients. The
drug's features and the special property required determine the type of oral dosage form to be
developed (Sohi et al., 2004). The formulation, such as syrups, solutions, elixirs, suspensions,
emulsion, tablets and capsules, are the usual types of oral formulations. Drug’s poor taste has
been discovered to be the biggest challenge by 90% of pediatricians in the U.S. (Kaushik and
Dureja, 2014). Taste disguising has become a precondition for unpleasant drugs to enhance
patient compliance, particularly in the pediatric and elderly population. Taste masking can
either reduce the oral solubility of the drug on consumption or reduce the drug particles
exposed to taste buds, thus decreasing the sense of bitter taste (Kinnamon, 2000). Various
physical and chemical methods frequently used for taste masking involve solid dispersion
system, ion exchange resin, complexation, effervescence, etc. which avoid taste palate contact
with bitter drugs. The selection of taste-masking technology depends upon the bitterness of
drugs and their physicochemical properties (Douroumis, 2011). The science of taste-masking
is gaining significance for refining the quality of the therapy for pediatrics and geriatrics. One
of the most palatable oral dosage forms is taste-masked medicated chewing gum, which can
provide both health & nutrition with an elegant approach.
3.1 TASTE

29
Pharmaceutical products are manufactured based on efficacy and safety, and pharmaceutical
professionals are generally uninformed of the sensory attributes related to taste optimization.
Tablets and capsules offer good protection from aversive characteristics and represent the
majority of orally administered drug products. In contrast, the food industry is dedicated to
developing palatable products and has highly refined approaches for optimizing the sensory
attributes (mouthfeel, aroma, texture, mouthfeel) of products (https://www.senopsys.com/top-
10-myths-of-taste-masking/). Due to differences in the regulatory framework, there is a slight
commonality between these two industries. The skill and science of taste masking of drugs are
built upon the notion of proper flavor construction, where multiple ingredients are well
combined and not distinctly recognized (Meilgaard, 1999). This is done by blending with
excipients and taste modifiers so that the acrimonious taste is no longer separately perceived by
the patient. Once this balance is achieved, various flavors can be selected based on patient
demographics, dosing frequency, and drug physicochemical properties. It is commonly thought
that a drug must be in solution to be perceived by the taste receptors located on the tongue
(Kelelson et al., 1993). However, some drugs, even at a very low concentration, can be
perceived. Even the drugs' coating is not sufficient for developing a palatable product as the
incomplete coating may lead to bitter taste reception. Thus, for developing palatable medicated
chewing gum coating should be accompanied with sweeteners and flavors.
3.1.1 Physiology of taste
The intellect of taste is mediated by taste buds, which is composed of thousands of taste
receptor cells clustered together and gives the sensation of taste by sensory neurons (Figure
3.1). The taste sensation is directed to the brain by a mechanism known as taste transduction
(Kulkarni et al., 2014). This process arises with the communication of food particles with the
G-protein coupled receptors in the taste buds, prompting gustducin protein release. This protein
triggers the effector enzyme phosphodiesterase 1A, which changes the intracellular levels of
secondary messengers such as diacylglycerol (www.umds.ac.vk/physiology/jim taste
olf.htm). The secondary messengers stimulate ion channels, including calcium and sodium.
The cell gets depolarized, instigating neurotransmitters' discharge that direct a nerve impulse to
the brain for a taste sensation.

30
 Figure 3.1 Physiology of taste buds
Four important sensations of taste have been designated as salty taste (edge, upper portion),
sweet taste (tip), sour taste (side back), and bitter taste (back). Sour taste is stimulated mainly
by acids, whereas bitter taste buds are stimulated by a variety of organic and inorganic
compounds such as calcium and magnesium. Scientists proved that damage to taste buds is
attributed to smoking, old age, eating of broiling food, vitamin B complex deficit, antibiotic
therapy, radiation, etc. Thus, the missing taste may lead to poor appetite and nutrition (Sharma
et al., 2012).
3.2 TASTE MASKING
Taste masking may be described as minimizing the detection of a disagreeable taste that would
somehow exist. The poor palatability and bitter taste are one of the main reasons for
noncompliance. Pharmaceutical formulations with amended taste features always deliver better
profits for the company. Taste perception is an imperative factor for the drugs administered
orally (Kaushik and Dureja, 2014). The various physicochemical methods for taste masking
involve microencapsulation, Cyclodextrin complexation, solid dispersion system, ion exchange
resins, etc. that prevents taste palate contact with bitter drugs (Sharma et al., 2012). To
effectively mask a taste, the type of interactions among excipients and changes occurring over
the tongue should be understood. Based on insight, taste-masking can occur by peripheral
interactions like taste hindrance or by central cognitive interactions like mixture repression.
Though, the third method comprises other technologies such as encapsulation or removing the

31
bitter target compound (Ebby, 1992). Several peripheral interactions can happen when one
compound would interfere with the taste signal mechanism related to other compounds, leading
to taste modification (Figure 3.2). A lot of research has been done to find the blockers for the
specific bitter taste, but as there are several receptors for bitter perception, it is difficult to find
a universal compound that can inhibit the stimulation of all the bitter taste receptors (Kale et
al., 2017, Kinnamon, 2000). Compounds like Zinc and Sodium salts at a certain concentration
have been identified to mask the bitter taste (Katsuragi et al., 1995). Researchers have found
that a lipoprotein, the combination of β- lactoglobulin (β-LG) & phosphatidic acid (P.A.),
selectively subdues the bitter taste response. Another exploration is receptor-based analysis,
where diverse compounds are screened directly on the target receptor for either arousal or
elimination of the taste signal (Maehashi et al., 2008). Mixture suppression takes place in the
brain and is related to central cognitive interactions.

Figure 3.2 Taste masking mechanism

The combination of sweeteners and flavors is generally used along with other taste-masking
methods for enhancing the dosage form's overall physicochemical characteristics. Aspirin has
been taste- masked by using various anesthetizing agents such as phenol and sodium phenolate,
which can momentarily desensitize the taste palate (Fu et al., 2004). Various factors that affect
the selection of taste-masking techniques are discussed below:
The degree of bitter taste

32
A slight contact to taste bud is adequate to perceive the bitter taste with highly bad-tasting
medicines. The sweeteners and flavors alone might not mask the tang of the bitter drug, which
is to be incorporated in the medicated chewing gum, which has been chewed for a long to be
effective. The polymer coating is a more competent technology for highly bitter drugs,
although coating defects can reduce the technique's efficiency (Garhwal et al., 2012).
Dose of the drug
The suitability of a taste masking technique depends highly on the dose of a drug. For example,
pediatric aspirin oral preparation was formulated by using sweeteners because of its low dose,
but a similar tactic failed to mask the bitter taste of drugs like acetaminophen due to its high
dose. In such circumstances, the coating technique is preferred along with sweeteners to attain
taste-masking, which can also be utilized to taste bitter drugs in the medicated chewing gum
formulation (Krise et al., 2004).
Dosage forms
Predictably, 50% of the populace has a problem with tablet swallowing. Chewable dosage
forms have come to rescue to solve these snags. Taste masking technologies such as particulate
coating, sweeteners, granulation, and microencapsulation can be used for the chewable and
combined with other pH modification skills to achieve taste masking. Other factors are drug
solubility and ionic characteristics of the drug. The bitter taste of tablets can be efficiently
masked by using polymer encapsulation that avoids the contact of the drug particles with the
taste buds. Yet, many researchers have made efforts to examine and discover the newer
technologies for bitter taste masking. The powders or granules for reconstitution cover a huge
share for the pediatric and geriatric market, which is exemplified by a large number of patents
(Maniruzzaman et al., 2012). Thus diverse technologies and approaches exist for taste
masking of granules or other dosage forms, are illustrated below:
3.2.1 Taste masking techniques
The mechanism behind the various physicochemical methods of taste masking involves the
prevention of interaction of the drug substance with the taste buds. The elementary method
includes the use of sweeteners & flavor boosters. But these methods have certain limitations
and failures (Kuchekar et al., 2003, Sohi et al., 2004). Various complex techniques that have
been known for taste masking include Cyclodextrin complexation, polymer coating, ion
exchange resins, solubility enhancing methods, use of liposomes, solid dispersions, viscosity

33
modifiers, multiple emulsions, use of anesthetic agents, etc. depending upon the type of
formulation to be developed. An ideal taste-masking technique should contain a minimum
number of machinery, require the least excipients, have no adverse implication on the drug's
bioavailability, and can be performed easily at room temperature. Zyck et al., (2003) patented
an antacid gum covered with high viscosity materials. The chewing gum formulation entails
gum base, plasticizers, sweeteners, flavoring agents, emulsifiers, colors, etc. The aqueous-
soluble part dissolves with a portion of flavors during chewing. The presence of basic calcium
salts or other excipients like sweeteners in the coating layer alters the taste and gum texture.
Monoammonium glycyrrhizinate, even in small quantities, is addressed to conceal the
acrimonious taste in chewable analgesics and multivitamins, cough syrups, oral antibiotics, and
antiseptics, etc. (Kurtz & Fuller, 1993). Taste masked chewable microcapsules of ibuprofen
has been prepared by employing air-suspension microencapsulation method, in which the
crystalline ibuprofen was present in core and Eudragit was used in coating (Shen et al., 1996).
The taste-masked granules/tablets of Amoxycillin trihydrate were prepared using
microcrystalline cellulose and hydroxypropyl cellulose (Olthoff et al., 1988). A compressed
chewable tablet of coated acetaminophen was developed using a blend of coating polymers
such as cellulose acetate butyrate, cellulose acetate, and Eudragit E-100, hydroxypropyl
cellulose, cellulose acetate; and polyvinyl pyrrolidone (Roche, 1991, Hoye et al., 1993).
Various methods are available to mask the undesirable taste of the drugs and are discussed
below and shown in Figure 3.3.
3.2.1.1 Taste masking with sweeteners and flavors
It is important to understand that only the water-soluble portion of the drug can produce the
taste sensation. The use of sweeteners & flavors is the underlying taste-masking technique,
particularly for pediatric formulation (Bhattacharjee et al., 2016). The relative sweetness of
commonly used sweeteners is discussed in Table 3.1 (Tripathi et al., 2011). This method,
however, is not very fruitful for extremely bitter water-soluble drugs, antibiotics, etc. Flavoring
and scenting agents are classified either as natural or artificial and are available as essential or
volatile oils, fruit juices, distilled fractions, concentrated extracts, syrups, alcoholic solutions,
etc (Tripathi et al., 2011). The various flavors used are discussed in Table 3.2 (Sohi et al.,
2004).

34
 Ion -exchange
resins

Buffering agents

Sweeteners and
flavors

Granulation

Cyclodextrin
complexation

Microencapsulation

Gelation

Figure 3.3 Taste masking techniques

The bitter taste of extract comprising Pogostemi Herba is masked by using Xanthan gum &
glycyrrhiza. Flavors, along with Monosodium glycyrrhizinate, have been employed to disguise
the harsh taste of guaifenesin. Foster et al., (2008) patented an invention of chewing gum
composition containing a gum base, active component, polymers, one or more sweetening, and
flavoring agents. Upendra et al., (2011) developed a medicated chewing gum of Promethazine
Hydrochloride using polyvinyl pyrrolidone synthetic gum, castor oil and glycerol as a
plasticizer and concluded that using castor oil as plasticizer gives a better release of a drug than
glycerol. Aslani et al., (2012) prepared the taste-masked medicated chewing gums of nicotine
using different sweeteners. Paradkar et al., (2016) formulated chewing gum of
Dextromethorphan using directly compressible gum base Health in Gum® with enhanced taste
by using a blend of sweeteners. Chandran et al., (2016) developed a taste-masked medicated
chewing gum of Indomethacin I.P. using the traditional melting process by using glycerol as a
sweetener. Shaikh et al., (2017) attempted to formulate a chewing gum for Dolasetron
comprising a gum base with fillers, sweeteners, coloring agents, plasticizers and antioxidants
which provide elegance and stability. Al-melh et al., (2019) patented an anesthetic gum to
alleviate pain from orthodontic surgeries, containing Prilocaine HCl and Lidocaine HCl as the
anesthetic components. The anesthetic chewing gum also included sweeteners, anti-adherents,

35
 lubricants, opacifiers, glidants, flavoring agents. The flavoring agents include peppermint oil
and a flavor enhancer, such as menthol.
Table 3.1 Relative sweetness of commonly used sweeteners
Relative sweetness
Sweeteners Properties
w.r.t sucrose
Glycyrrhizin 50 Highly expensive
Acesulfame potassium 137-200 Bitter after taste
Aspartame 200 Less stable in solution
Cyclamate 40 Banned, cancerous properties
Mannitol 0.60 Negative heat of solution
Lactose 0.16 Huge amount required in formulation
Slow onset of sweetness,
Sachharin 300-500
carcinogenic properties
Table 3.2 Flavoring agents used to mask the taste
Basic taste Flavoring agent
Sweet Bubble gum, vanilla, grapefruit
Coffee, liquorice, mint, chocolate, cherry,
Bitter
grapefruit, raspberry, peach, orange, lemon, lime

Acidic Lime, lemon, cherry, orange, grapefruit

Metallic Marsh, grape, mellow, berries, mints, guaran

3.2.1.2 Taste masking by granulation

Granulation is an economical, fast, and easily accessible taste-masking technology. This
technique can be used for taste masking of somewhat bad-tasting drugs. The mechanism involves
lowering the actual surface area of the bitter component, which interacts with the tongue upon
oral ingestion (Zelalem et al., 2009). Some frequently used excipients to accomplish taste
masking are low melting point waxes like glyceryl behenate, glycerol palmitostearate, and
hydrogenated castor oil, etc. Hayward et al., (1998) patented a granulated taste-masked
preparation consisting of a Non-Steroidal Anti-Inflammatory Drug (NSAID). The methacrylate

36
ester copolymers were used as coating polymers for taste masking, and the coated granules were
used in the formulation of chewable tablets, which had good taste and bioavailability.
3.2.1.3 Taste masking by Microencapsulation (Roche & Reo., 1994)
The process of coating of tiny dews of solid or liquid material with a layer of polymer is called
microencapsulation. Coating is a valuable technique for the fabrication of constant release
gastro-intestinal dosage forms and has key applications in disguising the unpleasant taste of drug
(Roche et al., 1994). Taste masking can be done by decreasing the drug's solubility in saliva by
coating it with an appropriate polymer as only the soluble fraction of the drug can generate taste
sensation. Mehta & Trivedi, (2011) formulated and evaluated Diphenhydramine Hydrochloride
medicated chewing gum via an eco-friendly gum base Corn Zein for treatment of motion
sickness. The formulations were made using a static concentration (35 % w/w) of diverse
plasticizers such as tributyl citrate, castor oil, oleic acid, triacetin, and different grades of
polyethylene glycol. Taste masking of bitter drugs can be done by using various combinations of
polymers as a single or multi-layer coat. Blends of water-insoluble polymers such as cellulose
ester, polyvinyl acetate, cellulose ethers, and water-soluble polymers such as
hydroxyethylcellulose, cellulose acetate butyrate, polyvinylpyrrolidone have been employed to
manage both the taste masking and in vitro release. Various hydrophobic polymers are also used
for coating bitter drugs. The microencapsulation may be done by using various techniques like
coacervation - phase separation, spray drying, air-suspension coating, spray congealing, multi
orifice - centrifugal process, solvent evaporation, and interfacial polymerization, etc. Swami et
al., 2012 formulated Dextromethorphan HBr chewing gums by using a directly compressible
gum base. It was then converted into spray-dried form and mixed with a Pharmagum M base to
enhance solubility and masking the drug's bitter taste. Mostafavi et al., 2014 formulated one
such Metformin gum to overcome its side effects, counting abdomen discomfort, vomiting,
diarrhea, etc. The drug was mixed with suitable sweeteners, and the mixture was freeze-dried,
spray-dried using diverse polymers or excipients. In a study by Sander et al., the possibility of
the spray drying technique in the formulation of Nicotine Bitartrate chewing gum was explored.
The drug was coated with polymers like hypromellose or alginate and then compressed into gum
tablets.
3.2.1.4 Ion exchange resins

37
Ion exchange resins (I.E.R.) are versatile and got significant attention from the researchers as a
drug delivery carrier. They find applications in developing various immediate and sustained
release oral formulations. Bitter drugs combine with ion exchange resins and remain intact at
salivary pH 6.8, making the drug unavailable for the taste sensation. These resins release the
drug only at acidic pH, which is present in gastric conditions (Jain et al., 2001). Some ion
exchange resins extensively used for taste masking are Amberlite IRP69, Amberlite IRP64,
Indion 214, Indion 204, Kyron T-104, and Kyron T-114. An effort has been made to formulate
taste-masked Lornoxicam chewing gum employing ion-exchange resin- Kyron T-114. This taste-
masked composite was then formulated into the medicated chewing gum by using directly
compressible gum base Health in gum® along with PEG 400 as a plasticizer.(http:/
/shodhganga. inflibn et.c.in/jspui/bitstream/10603/ 121763/14/15_chapter%2 06.pdf ).
3.2.1.5 Taste masking by inclusion complexation
The technique in which the guest molecule is enclosed inside the void of a host or complexing
agent is known as inclusion complexation. The complexing agent masks the bitter taste of drugs
by preventing its contact from taste buds, thereby decreasing the bitter taste sensitivity. It is a
sweet, non-toxic, cyclic oligosaccharide obtained from starch. Chaudhary& Shahiwala, (2012)
focused on taste masking of Cetrizine by inclusion complexation method using beta-cyclodextrin
as a taste masking agent. Various formulations were prepared by varying the drug- complexing
agent ratio and studied for taste abatement potential (Roy et al., 1994).
3.2.1.6 Taste masking using buffering excipients
It is known that the solubility of a drug largely depends on the pH of the solution. Thus,
buffering agents help in modifying pH conditions. Lichtneckert et al., 1973 reported in his
patent that the chewing of nicotine gum leads to a salivary pH of 3 – 5, which caused a harsh,
bitter taste to the palate. Thus, water-soluble buffering agents (pH-7.5) such as alkali
bicarbonates and hydro carbonates were employed to mask the taste. The enhanced absorption &
bioavailability is attributed to the increased availability of free base (non-ionized) nicotine.
3.2.1.7 Taste masking using gelation
Water-insoluble congealing on the surface of a formulation can also be used for taste concealing.
Sodium alginate can cause such phenomena in the presence of bivalent metal ions. Amiprolose
Hydrochloride tablet has been taste masked by smearing a base coat of sodium alginate, and
calcium gluconate was applied as an overcoat. Sodium alginate and bivalent calcium reacts in the

38
presence of saliva, resulting in the formation of water-insoluble gel, therefore masking the drug's
bitter taste. Acetaminophen granules were gushed with liquefied stearyl stearate and formulated
into a taste-masked chewable tablet (Kaning et al., 1997).
3.2.1.8 Effervescent agents
Effervescent agents have been used since long as taste-masking agents for oral formulations
such as powders, granules, etc. Lombardy et al., 2019 patented a novel effervescent chewing
gum that polishes teeth and freshens breath. The inventive chewing gum comprises a sodium
bicarbonate gum base encapsulated with a citric acid coating. Upon chewing, CO 2 is released,
which encourages the cleansing and mouth freshening properties of the gum. The medicated
chewing gum patented by Niazi et al., (1987) was developed which contained
Phenylpropanolamine Hydrochloride, chewing gum base, a taste-masking producer of
effervescence, and willingly a taste bud numbing agent such as benzocaine, spilanthol, etc.
3.2.1.9 Taste masking by adsorption
The adsorption is a process that makes the drug less saliva soluble so that the palate perceives
no bitter taste. The adsorbates are prepared by mixing the drug's solution with suitable
adsorbent followed by removing the solvent and drying the powder (Sampath et al., 2012).
3.2.1.10. Taste masking by prodrug technique
A chemically altered inactive drug precursor upon metabolism releases the biologically active
parent compound known as prodrug. Taste masking is done by altering the molecular geometry
of the parent compound so that when it combines with the geometry of taste receptor cells, no
bitter response is generated (Sharma et al., 2012). The molecular complexes can modify the
taste of the drug by decreasing the solubility of the drug. The advancement of a definite
universal inhibitor for bitter taste is necessary for taste optimization in the areas of food science
and pharmaceutical sciences. Since time, no such particular inhibitor is available because
constituents that obstruct bitterness of one compound will not influence the bitterness of the
other as they may share different receptors on the tongue (Jijo & Mathew., 2014). The taste-
masked medicated chewing gums are shown in Table 3.3.
Table 3.3 Taste masked Medicated Chewing gums by various techniques
Drug/Composition(s) Taste masking agents/Techniques Reference
Aloe Vera Sweeteners like aspartame, maltitol, xylitol, Aslani et al.,
flavors like eucalyptus, peppermint, banana,

39
 cola &cinnamon
Caffeine Sweeteners like aspartame, glycerin, xylitol, Aslani & Jalilian
mannitol, and sorbitol, flavors like
peppermint, cinnamon, cola, eucalyptus and
banana, cherry
Chlorhexidine Sucrose, sorbitol, flavors Lakshmi et al.,
Chlorpheniramine maleate Sucrose, liquid glucose, mannitol, aspartame Rajitha & Rao
Cetirizine Cyclodextrin inclusion complexes of drug Chaudhary &
Shahiwala
Dextromethorphan HBr DXM, Sucralose, Aerosil dispersed in ethanol Swami et al.,
to obtain spray-dried microparticles
(Microencapsulation)
Diltiazem Saccharin & Peppermint oil Pandit, A.
Dimenhydrinate HCl Liquid coating of sorbitol & glycerin and then Mehta & Trivedi
dry coating of sorbitol- Dry charging
Dolasetron Sorbitol, Sucrose & flavors Shaikh et al.,
Domperidone Maleate Sweeteners like mannitol, acesulfame, Paradkar et al.,
M.A.G., aspartame, Glycerhizza Glabra with
flavors
Diphenhydramine HCl Sweeteners like sodium saccharin Shete et al.
Famotidine Aspartame and menthol Mehmood et al.,
Ginger Xylitol, maltitol, aspartame, glycerol, lemon Aslani et al.,
powder, cinnamon, eucalyptus
Guaifenesin Beta- cyclodextrin complex Dabhi & Jeevani
Indomethacin Peppermint flavor Chandran et al.,
Lymecycline Liquid glucose, glycerin Jeyapriya
Magnolia Bark Peppermint oil Greenberg et al.,
Metformin Drug mixed with sweetener Acesulfame - Mostafavi et al.,
isomalt mixture and then further spray dried
or freeze-dried (Microencapsulation)

40
Neem Honey, sugar, liquid glucose, flavors Chanale &
Mishra
Levocetirizine Cyclodextrin complexation using Kleptoseor Marzuok et al.,
Dihydrochloride Captisol and ion exchange resins using Kyron
T-154 or Kyron T-314
Nicorandil Sucralose, aerosil, sorbitol, vanillin Yashaswini et
al.,
Nicotine Sweeteners (sugar, liquid glucose, glycerin, Aslani & Rafei
aspartame, stevia, licorice, or sodium
saccharin), Taste masking agents (zinc
acetate, sodium
acetate, or sodium chloride), Flavors
Promethazine HCl Dextrose, Peppermint oil Rao et al.,
Nicotine Spray-dried microparticles of Nicotine Sander et al.,
bitartrate using bioadhesive polymer like
hypromellose & alginate
Caffeine Co-encapsulation of caffeine with sweeteners Tyrpin et al.,
and further coating with water-insoluble or
water-soluble polymers
Oral hygiene gum Core contains bicarbonate, and coating Lombardy et al.,
contains encapsulated edible acid (
Effervescent agents)
Phenylpropanolamine Effervescent agents, taste bud desensitizing Niazi et al.,
HCl, Chlorpheniramine agents (benzocaine, spilanthol), sweeteners
Maleate and flavors

Scletium Tortuosum Xylitol, mannitol, sorbitol, cherry flavor Walt V.D.,

Salvia Divinorum Alkaline buffer, sweetening agent, Gonzalez et al.,
encapsulating buffer
Peppermint oil Encapsulated flavors like lemongrass oil, Demana et al.,
Peppermint oil with high-intensity sweeteners

41
 Benzydamine HCl Combination of aspartame- Acesulfame K Akbal et al.,
and menthol flavor
Amoxicillin Aspartame and Menthol Ranmale et al.,
Nystatin Drug-PEG 4000 solid dispersion, liquid Samiei et al.,
sorbitol, xylitol, aspartame and oily flavors
Chewing gum granules Sweetener, flavor encapsulated granules. Mikkelsen &
Schmidt

3.3 EVALUATION OF TASTE MASKING

Sensory analysis has been used for years to characterize flavors, odors, and fragrances (Tripathi et al.,
2011). Nowadays, the sensory analysis includes the subjective, objective, analytical, or hedonic methods.
Soutakagi et al., (1998) designed a multichannel taste sensor that detects taste like humans and comprises
numerous kinds of the lipid membrane. This automated technique can open new realms for taste sensory
evaluation. The taste-masked coated microspheres, ion exchange resinates can be assessed by calculating
the rate of release of the drug from the designed formulation. Further methods include human panel
testing, surgical method, spectrophotometric evaluation, etc.
3.3.1 Panel testing
This method constitutes a panel of about 5-10 human volunteers who are proficient for taste
estimation by using standard solutions having taste range from tasteless to very bitter. Then
numerical values are allocated to these solutions, which can provide a measurement of taste
response (Swarbrik et al., 1990). Caffeine medicated chewing gum was evaluated by Aslani et
al., 2013) for sensory properties by using a Likert scale. The Latin-Square design was employed
for the estimation of organoleptic features of the formulations like the taste, texture, stickiness,
flavors, etc. The opinions were recorded numerically, ranging from excellent taste to very poor
taste (0-5). A taste panel of volunteers measured the taste acceptability of Cetrizine chewing
gum, and the bitterness level was recorded. Volunteers assessed the product texture, consistency,
taste, and durability of the flavor released while chomping the gum. Similarly, evaluation of
taste-masked Indinavir-loaded pH-Sensitive microparticles was done in a blind randomized
sensory trial using ten fit human volunteers. Samples were scored using a numerical scale
(Chaudhary et al., 2012). One foremost challenge is masking the taste of the formulations
meant for pediatric and geriatric as they possess different physiology. A diversity of
psychophysical methods has been used to analyze taste sensation during different stages of

42
childhood. In 1988, Oster and Rosenstein established a method to visualize orofacial responses
by an infant, which is directly related to the intensity of taste sensations. Ingestive and suckling
reactions have been employed efficaciously to study response arrays. Countless types of
numerical methods which quantify the taste stimulus have been employed to regulate children’s
likings and their perception to taste (Mennela et al., 2013)
3.3.2 Animal testing-measurement of frog taste nerve responses
The neurobiological data from animal studies provide a potential similarity to human taste
perception. The brief-access taste test is done by giving various dilutions of the trial compounds
for seconds, and then licking response is measured as a behavioral pattern for taste stimuli. Most
commonly, the solutions are injected into the oral cavity of rats via surgically fixed cannulas. In
one of the taste recognition methods, mature bullfrogs are anesthetized by the intraperitoneal
route, and then the glossopharyngeal nerve is traced and cut proximally. The amplifier combines
the nerve impulses, and the peak elevation of the integrated nerve impulses is then recorded as
the degree of response (Figure 3.4). This method has limited applications due to its complex
process (Katsurgi et al., 1997).

Figure 3.4 Measurement of taste by frog nerve

3.3.3 Electronic E-tongue
E-tongue is a programmed taste recognizing equipment to perceive the extent of the bitterness of
drug substance. The device has a transducer which is made up of numerous varieties of lipid
membranes that can sense taste like humans (Lata et al., 2012). The electrical pattern generated
resembles the taste potential, which is then recorded by the detector. In a broad sense, lipids are

43
the most significant material for converting biochemical signals into electrical signals (Tagaki et
al., 1998). Quinine hydrochloride is used as the reference standard substance as it possesses the
highest bitterness level. Lipids commonly used are trioctyl phosphate, dioctyl phosphate, dioctyl
phosphate, methyl ammonium chloride, trioctyl methyl ammonium chloride. E-tongue is
particularly fabricated for taste analysis in the pharmaceutical industry, food, and beverage
sector. Taste of Injectable Lidocaine HCl dental formulation was evaluated by an Alpha MOS
ASTREE E-Tongue system (Wei et al., 2014). The diagrammatic representation of the E-tongue
method has been shown in Figure 3.5 (Patel et al., 2013).
3.3.4 Spectrophotometric method
This method determines the estimation of the drug concentration by using UV Spectroscopy. A
known amount of the taste-masked formulation is combined with purified water in a needle and
swirled for some seconds. The solution is then strained and analyzed for the drug concentration
using UV spectrophotometer. If the determined concentration is below the threshold level, then
the solution is assumed to be taste-masked (Gupta et al., 2010).

Figure 3.5 Evaluation of taste using e -tongue

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 CHAPTER 4
RECENT PATENTS AND APPLICATIONS OF MEDICATED CHEWING GUMS
Prerna Kaushik1, Md. Habibur Rahman2, Deepak Kaushik1*
1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana),
India-124001
2Department of Pharmacy, Southeast University, Banani, Dhaka-1213, Bangladesh
4. INTRODUCTION
Though medicated chewing gum has the potential to grow into a suitable unconventional
delivery system to mend patient conformity, it still vestiges as a field to be investigated.
Chewing gum is an elegant drug delivery system that provides medical benefits also. It can be
fabricated to offer diverse release profiles of the drug as it fulfills high-quality pharmaceutical
industry standards. The medicated chewing gum as a drug delivery system is suitable, portable,
and its agreeable taste enhances product adequacy and compliance (Heema& Stuti, 2010)
(Athanikar& Gubler, 2001). The nicotine gum remarkably influences the success of this
delivery system by providing product uniqueness in the marketplace. This uniqueness shows the
potential of chewing gum formulations holding a wide variety of pharmaceuticals and nutritional
supplements. Metformin chewing gum for the treatment of diabetes was developed as a result of
an alliance between two Pharma leaders Fertin and Generex Biotechnology (Chaudhary and
Shahiwala, 2010). Chewing gum applications can be varied due to patients’ dissimilar chewing
styles owing to different release profiles for the drugs leading to varied therapeutic efficacy. As
demonstrated by numerous patents and technological advancements, an attempt has been made
to formulate more palatable dosage forms that provide better patient agreement and an ultimate
therapeutic outcome. The current chapter enlists the most innovative and recent patents on
medicated chewing gums. The European patent office (http://ep.espacenet.com) and the United
States patent office (www.uspto.gov) provide various patents and their applications.
4.1 RECENT PATENTS ON MEDICATED CHEWING GUMS
Several techniques have been designated in the academic and patent literature for various
products and processes associated with medicated chewing gums. The limitations of traditional
methods have made the researchers file several patents in medicated chewing gums (Biswal &
Anantkumar, 2013). Today amended knowledge has made it conceivable to develop and
manufacture medicated chewing gum with predefined properties. The Indians & Egyptians used

51
to chew the resins of the trees in order to freshen breath. Dr. William F. Semple filed the first
commercial patent for chewing gum in 1869. The medicated chewing gum “Aspergum”
containing acetylsalicylic acid was marketed in 1924(Kaushik & Kaushik, 2019). However, this
delivery system was not accepted as a reliable drug delivery system until 1978, once nicotine
chewing gum became available (Rassing, 1996, William &Milind, 2012).
Goggin et al., 1951 patented a chicle chewing gum coated with amphetamine to provide a
predetermined release of the drug. The entire gum had been coated by numerous layers of sugar
to mask the bitter-tasting drug. Lombardy et al., 2001 patented oral hygiene gum in which the
core contains bicarbonate, and the coating contain encapsulated edible acid. The chewing
produces effervescence due to the reaction between acid and salt. This effervescence cleanses
and freshens the oral cavity by suppressing the mouth odor. Testa et al., 2001 patented a taste-
masked medicated chewing gum containing acetaminophen and ibuprofen employing
cyclodextrin complexation. West et al., (2003) developed a chewing-gum preparation for
treating gastroesophageal reflux disease, consisting of antacids, anti-flatulence agents, and an
inhibitor of acid production. Thus, an effective multifactorial treatment had been developed for
the treatment of GERD. Carsten et al., 2006 developed a tobacco alkaloid releasing chewing
gum comprising gum base and elastomers. The invention aimed to match the tobacco alkaloid
release with the release and absorption obtained from smoking a cigarette. Cherukuri et al.,
1999 developed a buffered chewing gum containing nicotine and gum base with an improved
release rate. Notably, the delivery system was capable of rapidly achieving a pharmacologically
effective concentration of the in the bloodstream within 5-10 minutes of chewing. Nijhawan et
al., 2007 developed a stick chewing gum containing antacids such as cimetidine, ranitidine, or
proton pump inhibitors such as omeprazole, pantoprazole or an acid pump inhibitor such as
Soraprazan, YH1885, AZD0865, etc. The composition was developed with the aim of decreasing
the unwanted side effects related to NSAID therapy. The invention by Amin et al., 2007
involved a novel chewing gum in the form of free-flowing granules. The granules were directly
compacted into chewing gum tablets at high speed using a traditional tableting machine. Bateddi
et al., 2009 developed a medicated chewing gum composition in which the dispersion of active
ingredient & gum base is coated by using a combination of water-soluble and water-insoluble
polymers. The drug was selected from the group consisting of nicotine, ibuprofen, paracetamol,
dimenhydrinate, ginger, vitamin C, acetylcysteine, ephedrine, D-pseudoephedrine, valerian,

52
ranitidine, chlorexidine, tribenzonium iodide, preferably nicotine while the soluble element was
sorbitol and the water-insoluble element was hydrogenated castor oil. The chewing gum tablet
controlled release properties with high stability. Andersen et al., 2013 formulated stable
medicament-containing chewing gum compositions comprising cetirizine and beta-cyclodextrin.
These compounds in oral formulation pose stability problems during production and storage.
Hence, efforts had been made to ascertain the reason for this stability problem in order to
counteract it. Cho et al., 2017 developed a chewing gum formulation involving antihistamines,
such as cetirizine, astemizole, loratadine and other components like plasticizer, sweeteners,
lubricants and flavors. The chewing gum's masticatory movement alleviates antihistamines' side
effects like somnolence and dryness of the mouth. Steenberg et al., 2016 patented a chitosan
chewing gum for decreasing the level of free phosphorus in the gastrointestinal juice. Chitosan
may be slowly released from the chewing gum and bound with phosphorus in the saliva
comprising bound phosphorus compound, which passes through the gastrointestinal tract without
entering the bloodstream. Thus, the amount of free phosphorus in the digestive juice may be
reduced. The most recent patents described by Al-Melh et al., 2019 focused on developing an
anesthetic medicated chewing gum containing Lidocaine HCl and Prilocaine for painless
orthodontic procedures. The anesthetic chewing gum included sweeteners, an anti-adherent, a
lubricant, an opacifier, a glidant, a flavoring agent, and a flavor enhancer. Neergaard et al., 2017
patented a chewing gum formulation comprising a cannabinoid. Most recently, a nicotine
chewing gum has been patented by Kristina et al., 2020. The invention related to a chewing
gum comprising Nicotine polacrilex with at least one sugar alcohol and at least one buffer
present in the coating. The aim of this invention was the fast and extended-release of nicotine
from the gum. DeLuca et al., 2005, patented the antiplaque chewing gum formulation to
suppress pathogenic bacteria, which contains a stable mixture of KSL-W, an antimicrobial
decapeptide with cetylpyridinium chloride. A center-filled or coated chewing gum has been
patented by Holy et al., 2011 containing probiotics such as Lactobacillus acidophilus to suppress
pathogens responsible for mouth odor. Gonzalez et al., 2012 also patented a nutrition
supplement chewing gum containing the botanical plant Salvia divinorum in order to awaken
human perception and consciousness such that the net psycho-spirituality is enhanced. The major
patents related to medicated chewing gum have been tabulated in Table 4.1 (Kaushik et al.,
2019).

53
Table 4.1 Patents on medicated chewing gum
Patent no. Inventor Title Year

US 2536168 Theodore C. Goggin Amphetamine chewing gum 1951

US2627493 Frederick G. Merckel. Fluorine chewing gum process 1953

Laszlo Reiner.
US 3316154 Harold M. Sellers Chewing gum containing gas and a 1967
medicament
US 5487902 Carsten Andersen , Chewing gum composition with 1996
Morten Pedersen accelerated, controlled release of
active agents
US 5846557 Barbara Eisenstadt, Chewing gum containing cough 1998
Penny A. Cash, and suppressing agent
Abraham I. Bakal
US 6235318 B1 Lombardy, Jr. Effervescent chewing gum 2001
EP 0909166B1 Testa, Emilio Process for making a medicated 2001
chewing gum with a pleasant taste
Containing an inclusion complex
US 6344222 B1 Subraman R. Medicated chewing gum delivery 2002
Cherukuri, System for nicotine

US 6444241B1 Henry T. Tyrpin, Caffeine coated chewing gum Product 2002

and process of making
US20040058033A1 Sozzi, Giuseppe. Chewing gum in powder form and a 2008
method of preparation
US0003490A1 Pardeep NijhaWan Anti-inflammatory conditions and 2007
prophylaxis against NSAIID
gastropathy

54
WO2006000232 A1 Carsten Andersen Tobacco alkaloid releasing gum 2006

WO2008104547 A1 Terence Cosgrove, Medicated chewing gum 2008

Beth Mary Foster,
Erol Ahmed Hasan,
Hongli Yang
US20120288450A1 Gonzales; Eduardo Chewing gum formula for enhancing 2012
Jose psycho-spirituality
US20160113304A1 Steenberg; Lars Chewing gum comprising chitosan for 2016
Christian Kure reduction of the level of free
phosphorus compounds in the
digestive juice
US20190054020A1 Al-Melh; Manal Anesthetic chewing gum 2019
Mansour Abu
US20190060229A1 Neergaard, Jesper, Medicated chewing gum comprising a 2017
Anayo Ogbonna cannabinoid
WO 012009A1 Thyresson Chewing gum comprising nicotine 2020
Kristina,Koll Gregory,
Nilgard Jill, Mcnally,
Gerard, Lindell
Katarina

4.2 RECENT APPLICATIONS OF MEDICATED CHEWING GUMS

Chewing gum is an elegant, discrete, and proficient drug delivery system which bids therapeutic
or nutritional benefits. Various researchers have made efforts to develop chewing gum for
various novel applications (Figure 4.1) (Bindi et al., 2011). Treatment of fungal diseases,
prevention of caries, dental health issues, smoking cessation, flavored, center- filled gums,
timed-release, and biodegradable chewing gums are some of the trendy products seen in the
future (Pittler et al., 2003). Some of the recent applications of medicated chewing gum have
been described below:

55
 Anxiety &
Depression Birth
Probiotic control
gum

Psychospirituality Hypophosphotemia

Menopause,
Anaesthetic virality

Tooth Novel Antibacterial

whitening Applications

Figure 4.1 Novel applications of medicated chewing gums

4.2.1 Birth-control gum
Birth control pills are being developed for women as medicated gum. Wamer-Chilcott Inc.
publicized a spearmint flavored birth control gum, Femcon- Fe. It is a chewable variety of Ovcon
35, a birth control tablet that has previously been in the market. Femcon- Fe contains progestin
hormone in a low dose so that it could reduce the related side effects such as depression, bloating,
irritability, and acne. (https://www.dailymail.co.uk/health/a rticle -421353/First-chewing-gum
contraceptive -pill-go es-sale- U-S.html )
4.2.2 Tooth whitening property
The ancient Egyptians used to cleanse & bleach their teeth by masticating the resins. But
nowadays, chewing gum serves this purpose. The commonly used bleaching agents are
carbamide peroxide or Hydrogen peroxide. Chlorine dioxide has well recognized sterilizing,
bactericidal, bleaching, and deodorizing properties. These properties led to the development of
chlorine dioxide chewing gum in order to provide therapeutic and cosmetic applications for tooth
whitening (Plaumann et al., 2012, Holme et al., 2000).
4.2.3 Probiotic gum
A center- filled or layered chewing gum containing inactive probiotics such as Lactobacillus
Acidophilus, Lactobacillus Sporogenes, Lactobacillus Plantarum, Lactobacillus Reuteri,
Lactobacillus Salvalarius etc. was patented and the formulation was proficient of having a good

56
stability. The chewing gum formulation was coated to avoid substantial loss of probiotics due to
excess heat, moisture, and pressure. The probiotics transported to the oral cavity provide oral
well-being to the patients by suppressing the pathogenic bacteria (Holly et al., 2011).
4.2.4 Psychospirituality
The study and relationship of intellect with hypothetical, moral, and intrapersonal observations is
known as Psychospirituality. A nutritional supplement gum formulation was developed for the
arousal of human cognizance and mindfulness such that the psycho-spirituality is boosted. The
formulation contained Salvinorin Alpha (A) as the principal active constituent, which is
extracted from the botanical plant S. divinorum. Gonzalez et al., (2012).
4.2.5 Anesthetics
Dental surgeries can lead to an undesirable effect on the patient's daily activities due to painful
procedures. This leads to the development of an anesthetic chewing gum to mitigate pain from
orthodontic procedures. The anesthetic chewing gum comprises lidocaine HCL and prilocaine
HCL as the anesthetic agents combined with a chewing gum base and sweeteners (Abu, 2019).
4.2.6 Hypophosphatemia
The invention is related to the development of chitosan chewing gum, which is a phosphorus
binding agent responsible for decreasing the level of free phosphorus in the digestive juice to
relieve hyperphosphatemia (Steenberg et al., 2016).
4.2.7 Anxiety and depression
Sceletium tortuosum is one of the most favorable medicinal plants for the management of anxiety
and depression. In one such a study, a directly compressible medicated chewing gum containing
S. tortuosum crude extract was formulated. Besides, the SeDeM Expert Diagram System was
employed to optimize the suitability of the excipients. (Vander et al., 2016).
4.2.8 Antibacterial
Lymecycline chewing gum was developed for the management of bacterial septicity.
Lymecycline is an antibacterial drug used in the treatment of Lyme disease, chronic bronchitis,
dental contaminations, and acne. Flavors and natural plant extracts of mint were employed in
chewing gum for breath freshening and relief of oral malodor (Jayapriya et al., 2018). In a
study, medicated chewing gum containing Magnolia bark extract (MBE) and its two chief
constituents, magnolol and honokiol, were formulated against bacteria liable for halitosis and
Streptococcus mutans, bacteria responsible for dental caries. The formulated chewing gum was

57
evaluated for germ kill inhibitory effect by using Listerine mouthwash as a reference standard
(Greenberg et al., 2007).
4.2.9 Menopause, Virality
A diverse range of herbal supplement chewing gums is manufactured by Zoft Gum Company,
such as stress, weight loss, menopause, breast enlargement, etc. Chewing gum for menopause
has been announced in 2007 that help to combat the menopausal symptoms such as insomnia,
mood swings, depression, palpitations etc. (https://www.pr.com/press-release/39659)
References
1. Al-Melh; Abu, M.M. (2019). Anesthetic Chewing Gum. US20190054020A1

2. Amin A, Norman G. (2007). Chewing gum formulation and method of making the same.
US7208186B2.
3. Andersan , C. (2006).Tobacco alkaloid releasing chewing gum. WO2006000232.
4. Andersan C. (2013) Stable MCG comprising cyclodextrin inclusion complexes.
US20130022652
5. Andersen, C. and Pedersen, M. (1996). Chewing gum composition with accelerated,
controlled release of active agents. US 5487902.
6. Athanikar, N.K., Gubler, S.A. (2001). Process for manufacturing a pharmaceutical
chewing gum. US6322828
7. Badetti R. (2009).Composition for medicated chewing gums: Process for manufacturing
the same and tablets so obtained. EP1162946
8. Bindi, G.C, Vipul, P.P, Tushar, R.D. (2011) .Medicated chewing gum: A Review.
Pharmatotur-Art ; 1047: 1-5.
9. Biswal, P.K., Anantkumar, P. (2013). An updated review on medicated chewing gum. Int.
J. Adv. Pharm. Bio. Chem; 2: 351-9.
10. Chaudhary, S.A, Shahiwala, A.F. (2010) Medicated chewing gum- A potential drug
delivery system. Expert. Opin. Drug. Deliv; 7(7): 871- 85.
11. Cherukuri, S.R., Pinney, J, M., Henningfield, J.E., Sasan, A., Cone, E.J., Shiffman, S.,
Gitchell, J., Malvestutto, C.D. (2002) .Medicated chewing gum delivery system for
nicotine. US 6344222 B1.

58
12. Cho, W. (2017) Formulation of medicated chewing gum comprising antihistamine.
KR101736038.
13. Cosgrove, T., Foster, B.M., Hasan, E. A., Yang, H. (2008). Medicated chewing gum.
WO2008104547 A1.

14. Eisenstadt, B., Cash, P. A., Bakal, A.I. (1998). Chewing gum containing cough
suppressing agent. US5846557.
15. Emilio, T. (2001). Process for making a medicated chewing gum with a pleasant taste
containing an inclusion complex. EP 0909166B1.
16. Goggin, T.C. (1951). Amphetamine chewing gum. US2536168A.
17. Gonzalez, E.J. (2012) Chewing gum formula for enhancing Psychospirituality.
US20110038915
18. Greenberg, M., Urnezis, P., and Tian, M. (2007) Compressed Mints and Chewing Gum
Containing Magnolia Bark Extract Are Effective against Bacteria
Responsible for Oral Malodor. J. Agric. Food Chem., 55: 9465–9469
19. Heema, N. and Stuti, G. (2010). Medicated chewing gums– Updated Review. Int. J.
Pharm. Res. Dev; 2(8): 66-76.
20. Holly, K., Pamela, M., Daniel, J. (2011). Thesis probiotic chewing gum method of
manufacture. US20110104239.
21. Holme, S.K., Luo, S.J. (2000).Chewing gum and confectionery compositions with
encapsulated stain removing agent compositions, and methods of making and using the
same. US6479071.
22. http://ep.espacenet.com.
23. https://www.dailymail.co.uk/health/article-421353/First-chewing-gum-contraceptive-pill-
goes-sale-U-S.html.
24. https://www.pr.com/press-release/39659.
25. https://www.uspto.gov/.
26. Jeyapriya, S. (2018). Formulation and evaluation of medicated chewing gum delivery of
lymecycline. A dissertation. Dr. M.G.R. Medical University, Chennai.
27. Kaushik, P., Kaushik, D., (2019). Medicated Chewing Gums: Recent Patents and
Patented Technology Platforms. Rec. Pat. Drug. Deliv. Form, 13: 184-191.

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28. Kristina, T., Gregory, K., Jill, N., Gerard, M., Katarina, L. (2020). Chewing gum
comprising nicotine. WO012009A1.
29. Lombardy, C.M., Lombardy, D.R. (2001). Effervescent chewing gum. US 6235318 B1.

30. Merckel, F.G., Laszlo, R. Fluorine chewing gum process.US2627493A.

31. Na DH, Faraj J, Capan Y, Leung KP, DeLuca PP. (2005) Chewing gum of antimicrobial
decapeptide (KSL) as a sustained antiplaque agent: Preformulation study. J. Control.
Release; 107(1): 122-30.
32. Neergaard, J., and Ogbonna, A., (2017). Medicated chewing gum comprising
cannabinoid.WO2017059859A1.
33. Nijhawan P. (2007). Medicated gumstick for treatment in anti-inflammatory conditions
and prophylaxis against NSAIDs gastropathy. US0003490.
34. Pittler MH, Stevinson C, Ernst E. 2003. Chromium picolinate for reducing body weight:
Meta-analysis of randomized trials. Int. J. Obes. Relat. Metab. Disord., 27(4): 522-9.
35. Plaumann, H., Castellano, C. (2012). Chlorine dioxide based gum. EP2429308.
36. Rassing, M.R, Jacobsen, J. (2003). Medicated gum modified release drug delivery
technology. New York: Marcel Dekker Inc.
37. Sellers, H.M. (1967). Chewing gum containing gas and a medicament. US3316154.
38. Sozzi, G. and Fabio, A. (2008). Chewing gum in powder form and a method of preparation.
US20040058033A1.

39. Steenberg, B. (2016) .Chewing gum comprising chitosan for use in reduction of the level
of free phosphorus compounds in the digestive juice. US20160113304
40. Tyrpin, H.T., .Russel, M.P., Witkewitz, D.L., Johnson, S.S., Ream., R.L., Coriveau, C.L.
(2002). Caffeine coated chewing gum product and process of making. US 6444241 B1.

41. Walt, V.S., (2016). Development and evaluation of a medicated chewing gum containing
Sceletium tortuosum. Dissertation. Masters of Science. Potchefstroom Campus. North-
West University. South Africa
42. West, D. (2003). Medicated chewing gum. US20030118691
43. William, P.V., Millind, T. (2012). A comprehensive review on medicated chewing gum.
Int. J. Pharm. Biomed. Res; 3: 894-907.

60
 CHAPTER 5
PATENTED TECHNOLOGY PLATFORMS FOR MEDICATED CHEWING GUMS
Deepak Kaushik1*, Prerna Kaushik1, Pankaj Kumar2
1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana),
India-124001
2Wipro Pvt. Ltd, Sarita Vihar, New Delhi, India-110044
5. INTRODUCTION
Platform technology is an important tool to improve productivity and quality in the process of
drug product formulation. The technology in amalgamation with a risk-based approach provides
a well-organized platform for product development. Besides, chewing gum expertise has been
growing steadily; therefore, plentiful pharmaceutical associations are now involved in
developing patented medicated chewing gum technology. An advanced drug delivery platform
provides patient benefits as well as increased revenue for a company (Kaushik et al., 2019). This
chapter covers a brief explanation of several patented technology platforms for medicated
chewing gum, including their fundamental principles, benefits, and uses. Fertin Pharma
(Denmark) is aimed at developing gum bases and develops Nicotinell® and NiQuitin® on
account of its spouse enterprises GSK and Novartis (Chaudhary et al., 2010). Revolymer has
patented the Rev7™ polymer, with an aim to develop biodegradable chewing gum (Deshpande
et al., 2013). Generex biotechnology developed a metformin chewing gum Metcontrol® for
diabetes prevention. Various commercial medicated chewing gum technology platforms are
Medichew, Chewmed®, Pharmagum®, Health in Gum® etc are enlisted in Table 5.1. Major
syndicates that are involved in the fabrication of medicated chewing gums are Enorama Pharma,
Fertin Pharma, Wrigley Jr., Axim biotechnology, SPI Pharma, Alkalon Pharma, etc.
5.1 PATENTED CHEWING GUM TECHNOLOGY BASED EXCIPIENTS
5.1.1 Medichew®
Fertin Pharma, Denmark, developed a multi-layered compacted chewing gum technology known
as Medichew® (https://fertin.com/). The finished product is based on its proprietary gum base,
consisting of sweeteners, flavors, color, active substances, etc. The manufacturing procedure is a
direct compression tableting process similarly employed in the manufacturing of conventional
tablets, and it is characterized as being less moist. The significant benefits of Medichew®
technology include multi-layered actives, diverse release profiles of actives, long-lasting flavor,

61
suitable for thermolabile actives, easy manufacturing process, etc. (Hyrup et al., 2005). The
major venture between AXIM Biotechnology and Fertin is the development of cannabinoid-
based Dronabinol chewing gum for the treatment of vomiting and nausea associated with
chemotherapy by using Medichew® platform (https://aximbiotech.com/pharmaceuticals/).

Table 1: Commercial medicated chewing gum technology platforms ((Kaushik et al., 2019)
Medicated Name and address of the Technology Commercial product
chewing gum company basis
technology
Medichew® Fertin pharma, Dandyvej 19 Multi-layered Energy 25, Caffeine(25mg),
DK-7100 Vejle, Denmark compressed Multivitgum, Svetol ™ (Diet
gum gum), Cavity gum
Skyepharma’s® Skyepharma, Vectura Group Multilayer Geogum
plc, One Prospect West tableting
Chippenham Wiltshire SN14
6FH, United Kingdom
Rev7® Revolymer®'Ltd Dock Road, Biodegradable Rev7®
MostynFlintshire CH89HE,
UK
HEALTH IN CAFOSA GUM SAU Powdered Health in Gum® Garcinia
GUM® Av. Diagonal 474, 1ª 8ª excipient Cambogia(200mg),
08006 Barcelona – Spain directly ABDENTALAC(Lactobacillus
compressible Plantarum CECT 7481,
technology Lactobacillus CECT 7480)
CHEWMED Enorama pharma AB, A cold and dry Nico bright, nicotine gum (2, 4
Sodergaten 3, sec 21134 powder mg)
malmo, Sweden

5.1.2 Skyepharma’s ® geogum

‘Geogum' is the patented chewing gum of Skyepharma, which is apropos for either local or
systemic transport of drugs. The proprietary medicated chewing gum technology uses the

62
multilayer tableting approach. A combination of coatings modulates the release rate of the drug
and excipients when the gum is chewed. Their chewing gum delivery system is patient-friendly,
opportune, and discreet, which provides delivery for the drugs that are degraded or metabolized
by the gut, thereby avoiding the first-pass effect. This consents the use of lower doses of the
drug, thus providing rapid delivery and better bioavailability of the drug.
(https://www.skyepharm a.fr/medicated-chewing-gum/).
5.1.3 Rev7®
Revolymer ® has solved the problems associated with the dumping of the cud after munching
the gum. Its amphiphilic polymer Rev7®, when combined with a gum base, can provide multi-
facet aids like increased chewability and biodegradability of the gum
(http://www.revolymer.com/). It is made up of polyisoprene units and polyethylene oxide (PEO)
(Figure 5.1). This solves a very expensive and ecologically challenging problem. Revolymer®’s
gum can be easily removed from the garments using soap and water and degrades into
biodegradable and inert materials (https://www.ipgroupplc.com/media/portfolio-
news/2010/2010-10-04a). Behl et al., 2015 developed chewing gum formulation containing
Lansoprazole by using Revolymer’s® hydrophilic polymer Rev7® and buffering agents. The
drug was complexed with β-Cyclodextrin and was investigated for the type of dissolution
medium, pH, chew rate, release rate, and stability. The optimized formulation containing
potassium carbonate provided the paramount release of drug from the gum and also improved
buccal absorption.

Figure 5.1 Chemical structure of PIB (Polyisobutylene) and PVA (Polyvinylacetate)

5.1.4 Pharmagum®
The directly compressible chewing gum component can make the manufacturing process fast.
The use of this technology can conquer the limits of conventional and freezing methods.

63
PHARMAGUM®, a free-flowing compactable gum system developed by SPI Pharma, is a
combination of sugars with a gum base (http://www.spipharma.com/ProductsFolder/12
0ParmaGum/120Pharmagum.html). The powder can be compressed into a gum tablet using a
traditional tablet machine, thus allowing quick and easy manufacturing of chewing gum. They
can be considered safe (GRAS) as they comply with Food Chemicals Codex stipulations and the
FDA. It is accessible in three grades, namely S, M, and C., containing a different proportion of
gum base and sweetener. Pharmagum® M contains 50% gum base. The nicotine released from
the directly compactable formulation is more as compared to the gum produced by the
conventional process. The formulations made with this technology are analogous to tablet in
appearance and are ten times durable. Swamy et al., 2012 prepared the chewing gum
formulations containing Dextromethorphan hydrobromide with an aim to overcome the first-pass
effect, ease of administration, reducing the risk of overdosing, and for faster systemic absorption.
The drug was then spray dried and incorporated into Pharmagum ®M base to enhance solubility
enhancement and disguise the drug's bitter perception.
5.1.5 Health in Gum®
Cafosa developed a unique, ready to mix powdered excipient, Health in Gum®, that authorizes
to develop compacted chewing gum. The directly compressible powder can be mixed with the
active ingredient and developed into a gum tablet using in-house pharmaceutical facilities. It has
an excellent flow and a faster drug release profile (www.healthingum.com). The heat-sensitive
and water-sensitive drugs can be utilized through this technique. Other compensations include
patient compliance, quicker action, systemic and local effect, patient’s control over treatment,
reduced exposure to gastrointestinal side effects caused by actives. It is also available in three
grades HIG 01, 02, and 03, which differs in the composition of gum base, sorbitol, and
plasticizer (http://www.cafosa.com/EN_Health_in_Gum). Paradkar et al., (2016) formulated
a taste-masked, directly compressible medicated gum of Dextromethorphan Hydrobromide using
Health in Gum® (gum base) with a blend of sweeteners. Chaudhary et al., 2012 hypothesized
the effect of directly compressible powder Health in Gum on medicated chewing gum of
Cetirizine. The study relied upon the fact that Cetrizine is a BCS class I drug and will be easily
released from the gum into saliva and deliver a quick-onset of therapeutic action devoid of
producing sedation as a side effect.
5.1.6 Chewmed®

64
The ChewMed® technology by Enorama Pharma is a modern technology platform suitable for
the production of medicated chewing gums. The ChewMed® expertise utilizes high pressure and
low-temperature manufacturing process which can protect the thermolabile actives from
deterioration. The gum has improved sensory properties and has an aesthetic appearance.
Another feature is the crispy coating, which results in an unusual, refreshing taste perception
when munched upon. The chewing gums prepared by this technology have a greater ability to
carry different actives, better and longer taste, striking appearance, and great potential for
multiple applications (https://www.enoramapharma.com/our-offer/chewmedr-platform/).
5.2 MAJOR PHARMA COMPANIES FOR MCG
5.2.1 Fertin Pharma
Fertin Pharma, Denmark, is the world’s leading third-party manufacturer for nicotine chewing
gum having at least 30 years of experience (https://fertin.com/applicationareas/#Nicotine). It
has an extensive past in developing good quality and innovated chewing gum. Fertin Pharma in
2013 opened a GMP approved Research & Development center in Mumbai to help in the
development of novel chewing gum skills. In 2014, the Nicotine Science Center was established
in order to develop a therapy for nicotine replacement and smoking cessation. Fertin Pharma
opened a high-tech manufacturing facility in Goa for the development of nicotine gums in
agreement with cGMP. It serves as a national market for export to evolving markets
(https://en.wikipedia.org/wiki/FertinPharma). An innovative and consumer-friendly bi-
layered compressed chewing gum is among the best in the field with its extraordinary taste and
texture with an escalating mandate for unconventional drug delivery systems. In this technology,
Fertin’s patented gum base is mixed with the API, excipients, and compacted into a bi-layered
tablet. CAVITYGUM is a chewing gum concept targeting dental health that includes several
active ingredients like Magnesium, Vitamin D, Calcium, and Fluoride. The energy gums are
ENERGY 25, ENERGY-32, ENERGY 50, 100, etc. IMMUNEGUM, MULTI VIT GUM,
LACTIGUM, SAFFRAGUM, DIETGUM, Q10 gum, CAVITYGUM, SENSITIVEGUM are
some of the trendy gums for immunity, anti-stress, weight management, Heart health, oral care,
etc.
5.2.2 Medcan Pharma (https://www.medcanpharma.com/)
MedCan, a fellow company of Fertin focusses on developing benign, effective, and suitable
cannabinoid products with a controlled release technique. The directly compressible technology

65
efficiently releases the lipid-soluble cannabinoid moiety from the gum base. The multi-layered
technology provides a diverse release of the actives at variable rates. The compacted gum can be
combined with a crispy flavored Zapliq® delivery system, which softens when chewed and
provide a unique mouthfeel (https://www.medcanpharma.com/delivery_systems/#
Compressed-gum).
5.2.3 Axim Biotechnology
AXIM® Biotechnologies is a trailblazer in the research and development of cannabinoid derived
products and oncological therapeutics. AXIM® Biotechnologies, patented a method to develop
chewing gum composition of cannabinoids and nicotine in order to alleviate tobacco smoking
and neurodegenerative diseases (https://www.prnewswire.com/news releases/medicalm
arijuana-inc-investment-company-axim-biotechnologies-receives-new-us-patent-issuance-
for-chewing-gum-comprising-cannabinoids-and-nicotine-301037331.html)
5.2.4 Alkalon Pharma
Alkalon is a self-governing research company based in Denmark. The enterprise specializes in
the development of medicated chewing gum formulations. Its domestic R&D occurs in a trivial
non-GMP laboratory, and all non-core activities are subcontracted. The company has lately
developed and registered a collection of new and improved nicotine polacrilex chewing gums
through licensing (http://www.alkalon.com/sites/default/files/2012.09.25%20Article%20
Medicated%20c hewing% 20gum%2 0 delivery%20systems.pdf)
5.2.5 Enorama Pharma
Enorama Pharma is a medicinal corporation whose headquarter is in Malmö, Sweden. The
company’s commercial notion is to develop medicated chewing gums as private label products.
Its chief artifact is nicotine gum. But some probable and future applications include pain relief,
allergies, and colds (www.enorama.se).

References
1. Deshpande T, Ramesh G, Deshmukh K. (2013). Medicated chewing gum -an emerging
intra-oral dosage form. Am. J. Pharm. Tech. Res; 3(1): 48-66.
2. Chaudhary SA, Shahiwala AF. (2010). Medicated chewing gum- A potential drug
delivery system. Expert. Opin. Drug. Deliv; 7(7): 871- 885.

66
3. Kaushik, P., and Kaushik, D., (2019). Medicated Chewing Gums: Recent Patents and
Patented Technology Platforms. Rec. Pat. Drug. Deliv. Form, 13: 184-191.
4. https://fertin.com/
5. https://aximbiotech.com/pharmaceuticals/
6. Hyrup B, Andersen C, Andreasen LV, Tandrup B, Christensen T. (2005).The MediChew
technology platform. Expert Opin Drug Deliv; 2(5): 927-33
7. https://www.skyepharma.fr/medicated-chewing-gum/
8. https://www.ipgroupplc.com/media/portfolio-news/2010/2010-10- 04a
9. http://www.revolymer.com/
10. Bahl P. (2015). Development of medicated chewing gum formulations for the delivery of
a poorly soluble drug. Doctoral thesis, University of Huddersfield; 1-235.
11. Pharmagum-M Directly compressible gum. http://www.spipharma.com /ProductsFolder/
120ParmaGum/120Pharmagum.html.
12. Swamy, N.G.N., Shilpa, P, Abbas Z. (2012). Formulation and characterization of
medicated chewing gums of dextromethorphan hydrobromide. Indian Drugs; 49(12): 29-
35.
13. www.healthingum.com.
14. http://www.cafosa.com/EN_Health_in_Gum.
15. Paradkar M, Gajra B, Patel B. (2016); Formulation development and evaluation of
medicated chewing gum of anti-emetic drug. Saudi. Pharm. J., 24(2): 153-64.
16. Chaudhary SA, Shahiwala AF (2012). Directly compressible medicated chewing gum
formulation for quick relief from common cold. Int. J. Pharm. Investig; 2(3): 123-33.
17. https://www.enoramapharma.com/our-offer/chewmedr-platform/
18. https://fertin.com/application_areas/#Nicotine.
19. https://en.wikipedia.org/wiki/Fertin_Pharma.
20. https://www.medcanpharma.com/.
21. https://www.medcanpharma.com/delivery_systems/#Compressed-gum.
22. https://www.prnewswire.com/news-releases/medical-marijuana-inc-investment-
company-axim-biotechnologies-receives-new-us-patent-issuance-for-chewing-gum-
comprising-cannabinoids-and-nicotine-301037331.html.

67
23. http://www.alkalon.com/sites/default/files/2012.09.25%20Article%20Medicated%20c
hewing%20gum%20 delivery%20systems.pdf.
24. www.enorama.se.

68
 CHAPTER 6
EVALUATION OF MEDICATED CHEWING GUMS
Prerna Kaushik1, Deepika Purohit2, Ravinder Verma 1, Deepak Kaushik1*

1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana),

India-124001
2 Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, India

6. INTRODUCTION
Medicated chewing gum is a drug delivery system that contains diverse, active pharmaceutical
ingredients (API) mixed together with a water-insoluble gum base. The extensive recognition of
medicated chewing gum as a therapeutic dosage form demands the proper rigid techniques to test
its biopharmaceutical quality. The European Pharmacopoeia described the product quality tests
for medicated chewing gums, including assay, content and mass uniformity, in vitro dissolution
studies, and ex-vivo buccal permeation studies. Some of the non-official tests include texture
evaluation, product sensory properties, coatings impurities, water content, stability studies, etc.
As USP does not have any official apparatus for in vitro dissolution analysis, the apparatus is
developed by the manufacturer, which is not described in the official monograph (Gajendran et
al., 2008).
6.1 OFFICIAL TEST
The official methods for testing medicated chewing gums have been defined in the 8th edition of
the European Pharmacopoeia, which analyses the product quality (European Pharmacopoeia,
2014).
6.1.1 Uniformity of content
This test is done to confirm the content uniformity in a single-dose product. Test A, B, and C are
three content uniformity test described in the European Pharmacopoeia. Test A is for tablets,
although tests B and C are envisioned for transdermal patches and capsules, correspondingly. As
medicated chewing gum is a compact dosage form, it should comply with test A. It is calculated
by determining the active ingredient content in ten arbitrary chewing gum items. Each chewing
gum passes the test if drug content lies within the prescribed range (85 -115%). The medicated`

69
chewing gums of Chlorpheniramine Maleate were evaluated for hardness, weight variation,
stickiness, color, drug content, etc. by Rajitha et.al., 2016.
6.1.2 Weight variation test
Twenty medicated chewing gums are selected arbitrarily to carry out weight variation test. Their
individual weights are calculated and hence the average weight. Then, the percentage of
deviance is calculated by using the average weight. Each two gum entities should not differ from
the mean weight by more than 7.5% of the gums with a mean weight ≥ 300 mg and 10% for
gums with an average mass ≤ 300 mg (Haghbani et al., 2018). Then the percentage weight
variation is calculated by using the formula.
Weight variation (%) = (Weight of single MCG/ mean weight of 20 MCG) * 100
6.1.3 Friability
Ten gum units are arbitrarily selected for the friability test. Gums are weighed initially (W
initial) and placed in a Roche friability tester, which rotates 100 times at 25 rpm. Gums are then
wiped and weighed again (W final). The friability percentage (F %) can be calculated by using
the below formula. MCGs clear this test if percentage friability is less than 1%.
F% = (Winitial–Wfinal/Winitial)* 100
6.1.4 In vitro drug release
A lot of research has been done to describe the complex in vitro drug release mechanism of
medicated chewing gums to analyze the effect of critical manufacturing variables. The versatility
of the chewing apparatus has been demonstrated by using various actives like nicotine,
dimenhydrinate, meclizine and xylitol, respectively by Kvist et al., 1999. The release of caffeine
from the gum base was examined by Aslani et al., 2013, using the chewing gum dissolution
apparatus. The release rate of caffeine chewing gums increased with time and reached 88% after
30 minutes. The European Pharmacopoeia has approved an in vitro dissolution apparatus which
simulates the human masticatory movement to govern the drug release from chewing gums. The
gum is put in a tiny chewing compartment that contains a known capacity of buffer solution at a
particular temperature (European Pharmacopoeia, General Monograph 2.9.25, 2008). The
rate of drug release is affected by the chewing angle, mechanical forces, chewing rate,
wettability, temperature, and water permeation, which helps change the inactive gum to the
active form. According to the official monograph, the rate of drug release is directly
proportionate to the chewing frequency and aqueous solubility of the drug and is indirectly

70
proportional to the quantity of the gum base (Shah et al., 2006, Pagare et al., 2012).
Mathematically,
Rate of drug release (α)= chewing frequency * water solubility of the drug
Mass of gum base
Apparatus A (Compendial—Ph. Eur).
The dissolution apparatus A has been approved in 2000 by the European Pharmacopoeia and is
shown in Figure 6.1. The mastication process is mimicked by placing the chewing gum in a
temperature-regulated chewing compartment in this device. The gum here is exposed to
automated forces by two parallel pistons that swap around in antithetical direction in a continual
speed. A vertical piston (tongue) ensures the suitable location of the gum. The chew rate,
medium volume, jaw distance, and twisting movement are some of the variable factors whose
effect can be evaluated. The official parameters of phosphate buffer (20 ml, pH 6) solution with a
40-mL capacity chewing compartment, chew rate (60/minutes), and chewing time (10-15
minutes) are used (European Pharmacopoeia, 2014).
Apparatus B (Non compendial—Wennergen)
Wennergren designed this apparatus with numerous research validating its use (Figure 6.2). This
apparatus considered the effect of rotary movements and the temperature of the medium on drug
release. It consists of chewing chambers tailored with vertical pistons signifying the higher and
lower chewing jaws. The gum is positioned on the lower jaw. The to and fro locomotion of the
lower jaw in amalgamation with a twisted movement of the upper jaw provides adequate
agitation and mastication (Kvist et al., 1999).

Figure 6.1: Dissolution apparatus as per European Pharmacopoeia (Apparatus A)

71
 Figure 6.2: Single module chewing apparatus (Apparatus B)
6.1.5 In vivo ‘chew-out’ studies- Salivary and urinary profile studies
The in -vivo chew out studies can be done by using a panel of human volunteers. The drug
present in the gum is first released in saliva and is either absorbed via oral mucosa or, through
the gastric membrane. The amount of salivary secretion, salivary pH, drug's salivary solubility,
the fate of drug absorption are some of the important factors which strongly affect the drug
release rate. The in vivo release of Cetrizine from chewing gum was investigated using human
panels trained to chew the gum sample for 15 minutes. The masticated gums were then collected
from volunteers and analyzed by a UV spectrophotometer at 230.4 nm for the remaining drug
content. The quantity of drug released during chewing was calculated by deducting the quantity
of the gum's remaining drug content from the total drug content (Chaudhary et al., 2012).
The urinary analysis is used for the drugs which are expelled through urine. Human panels are
instructed to collect their urine on various time intervals after chewing a piece of gum. Then the
collected sample is investigated by appropriate analytical techniques. The buccal absorption test
was also done using Dextromethorphan chewing gum. The saliva after chewing was then diluted
appropriately and analyzed at 278 nm by UV spectroscopy. The test disclosed that 79.6% of the
drug was buccally absorbed within 15 min at pH 6.0 (Swami et al., 2012).

72
6.1.6 Ex-vivo buccal permeation study
This study is done to calculate the total amount of the drug penetration through the buccal
membrane using a Franz diffusion cell, shown in Figure 6.3. Chaudhary et al., (2012)
performed the buccal permeation studies on Cetrizine. In this method, buccal mucosa of various
animals like pig, monkey, or goat is taken and positioned between the salivary chamber (donor)
and a blood chamber (receiver) of the Franz diffusion cell. The phosphate buffer of salivary pH
6.8 is packed in the donor section, and phosphate buffer of blood pH 7.4 is filled in the receiver
section. The mean quantity of the drug, which is released from the optimized preparation after 30
minutes of munching, is taken from the receiver section and analyzed by the UV-
spectrophotometer.

Figure 6.3: Franz diffusion cell

6.2 UNOFFICIAL TESTS
Medicated chewing gum offers certain other non-official quality tests, which include
organoleptic, sensory, mechanical testing. Some of these tests are described below:
6.2.1 Estimation of organoleptic properties
Organoleptic properties affect the sense, acceptance, taste, marketing, and visual properties of
the formulation. For chewing gum evaluation, various factors like softness, stickiness, bulk
volume, and taste perception need to be checked (Pagare et al., 2012).

73
Taste acceptability of Guafenesin chewing gum was measured containing human volunteers
using various scales .The following scale was used:+ = very bitter +++ = slightly bitter ++ =
moderate to bitter ++++ = tasteless or taste masked (Dabhi et al., 2019).
6.2.2 Evaluation of mechanical (tensile) properties of chewing gums
In this, gum samples are exposed to a strain until they break. The load required for a stretch
before the breakage is noted by the computer. The mechanical stress and strain can be obtained
by the formula:
Stress (σ) = P/Ao
Strain (e) = Δl /lo
Where P= Weight (load)
Ao= Initial cross-sectional area
Δl= change in length
Lo= Initial gage length
The initial part of the curve follows Hook’s law, where the ratio of stress to strain is constant,
and a linear correlation can be observed. The major considerations found from the test are yield
strength, tensile strength, and fracture strength. Vernier caliper measures the thickness and
diameter, and organoleptic properties of the medicated chewing gums are estimated visually
(Haghbani et al., 2018).
6.2.3 Texture analysis
This analysis deals with the assessment of mechanical features in which a material is exposed to
a definite force, and a distortion curve is produced. The texture analysis of chewing gum is done
using Brookfield® QTS-25 texture analyzer. The distortion curve is interpreted, and the peak
load necessary for distortion of medicated gum is calculated. The texture analyzer has been
shown in Figure 6.4.
6.2.4 Stability
The stability of chewing gum lies in the fact that it has low moisture content (2-5%) which does
not react with other excipients. The various challenges in the production of chewing gum are its
storage settings and shelf-life (Aslani et al., 2015). Stability testing was performed on
Chlorohexidine chewing gum according to ICH procedures by storing at 25°C/60%RH and
30°C/65% RH for 30 days to determine the amount of deterioration (Lakshmi et al., 2014).

74
 Figure 6.4: Brookfield® QTS-25 texture analyzer

References
1. Aslani A, Rostami F. (2015). Medicated chewing gum, a novel drug delivery system. J.
Res. Med. Sci; 20:403-411.
2. Aslani, A, Jalilian, F. (2013).Design, formulation and evaluation of caffeine chewing
gum. Adv. Biomed. Res; 2:72
3. Chaudhary, S. A. & Shahiwala, A. F. (2010). Medicated chewing gum- a potential drug
delivery system. Exp. Opin. Drug. Deliv., 7: 871-885.
4. Dabhi, P., Jivani., N.,(2019). Design and Evaluation of Guaifenesin Medicated Chewing
Gum for Cough Relief. IJESC., 9(5):22668-22677
5. Gajendran J, Kraemer J, Langguth P. 2012.In vivo predictive release methods for
medicated chewing gums. Biopharm .Drug. Dispos ; 33(7):417–24.
6. General Monograph 2.9.25: Dissolution Test for Medicated Chewing Gums. European
Pharmacopoeia 6th Ed. European Directorate for the Quality of Medicines,
Council of Europe. Strasbourg, France, 2008.

75
7. Hagbani, T.A., and Nazzal, S., (2018). Medicated Chewing Gums (MCGs): Composition,
Production, and Mechanical Testing. AAPS Pharm. Sci. Tech., 19(7): 2908-2920.
8. Kvist C, Andersson SB, Fors S, Wennergren B, Berglund J. (1999). Apparatus for
studying in vitro drug release from medicated chewing gums. Int. J. Pharm.;189(1):57–
65
9. Lakshmi, S.V., Yadav, H., Mahesh, K.P., Uniyal, S., Ayaz1, A., Nagavarma, B.V.N.,
(2014). Formulation and evaluation of medicated chewing gum as antiplaque and
antibacterial agent. J. Young. Pharm., 6(4):3-10.
10. Pagare, P. K., Satpute, C. S., Jadhav, V. M. & Kadam, V. (2012). Medicated chewing
gum:
A novel drug delivery system. J. App. Pharm. Sci., 2:40-54.
11. Pharmacopoeia E. General monograph on dosage foms: chewing gum, medicated.
European directorate for the quality of medicines. 8th Ed: Council of Europe; 2014. p.
781.
12. Rajitha, K., and Rao., Y.M. (2016). Formulation and evaluation of medicated chewing
gum of chlorpheniramine maleate by melting method. WJPPS, 5(5): 1322-1329.
13. Shah., K. R., Mehta., T.A. (2014). Medicated Chewing Gum- A Mobile Oral Drug
Delivery System, IJPRIF, 6(1):35-48
14. Swamy, N.G.N., Shilpa, P., Abbas, Z., (2012). Formulation and characterization of
medicated chewing gums of dextromethorphan hydrobromide. Indian Drugs., 49(12).

76
 CHAPTER 7
PACKAGING & REGULATORY ASPECTS OF MEDICATED CHEWING GUMS
Prerna Kaushik1, Ritu Kaushik1, Parijat Pandey2, Deepak Kaushik1*
1, 1*Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana),
India-124001
2Shri Baba Mastnath Institute of Pharmaceutical Sciences and Research, Baba Mastnath
University, Rohtak (Haryana), India – 124001

7. INTRODUCTION
The chewing gum packaging preserves the aroma and flavor and enhances the storage and shelf-
life of the product. It also stabilizes the product by providing moisture retention. There are
various graceful packaging approaches with multiple variations. Blister packs, aluminium foil
packs, cardboard packs, and plastic containers are trendy packaging materials available for
chewing gums. An automated wrapping machine does the wrapping and sealing of the gums. The
blister pack formed may be sealed with a foil at the back by using the heat. The temperature and
relative humidity optimized for the gum's manufacturing and packing is about 20-25°C and 57%,
respectively (Pagare et al., 2012). Packaging has a considerable amount of advantages such as
consumer attraction due to elegant design, pleasant taste, content protection, easy transportation,
and storage improvement, etc. The insight of chewing gums as a drug delivery system has gained
popularity. Presently, medicated chewing gums are recognized as approved drug delivery
systems by the U.S. Pharmacopoeias (USP) and European (Ph. Eur). The medicated chewing
gums can be utilized for various drugs, such as Cetirizine, Dextromethorphan Hydrobromide,
Dimenhydrinate Hydrochloride, Miconazole, Aspirin, Nicotine, Caffeine, and Nystatin, etc. as
described by the research literature. Oral health, motion sickness, smoking cessation, pain relief,
obesity, diabetes, nutritional supplement are some of the applications of medicated chewing
gum. (Haghbani et al., 2018). This chapter discusses the packaging, regulatory aspects of
medicated chewing gums in various countries like the USA, E.U., Australia, etc.
7.1 PACKAGING OF CHEWING GUMS
Medicated chewing gum is a very stable product as it contains less moisture and thus not very
reactive. But this makes the product hygroscopic and affect its texture. The little amount of water

77
in the chewing gum also prevents microbial growth during storage and enhances its shelf life. In
order to prevent deterioration, various antioxidants are added to the chewing gum. Besides,
polymer coating and appropriate packaging can be used to enhance stability against oxidation.
The temperature of 50–60° C may create a stability issue for thermo-sensitive drugs. Thus, to
solve this problem, temperature and chewing gum manufacturing methods can be varied (Shah
et al., 2014).Chewing gums can be molded into various forms like cut- wrap, stick- tabs, pellets ,
hollow balls, liquid-centered gums, compressed gums, etc. (http://www.cafosa.com/
EN_Differenttypes_of_chewing_gum ). The gum bases required for cut – wrap, sticks, and tabs
chewing gum need a firm elasticity to resist the elongation during cooling. Gum bases for the
laminated product should have the necessary plasticity and hardness for shaping and wrapping,
respectively. Coated chewing gum generally has a higher gum base than cut and wrap gum.
Glucose contents should be adjusted to maintain the required hardness for the packaging.
Individual wrapping in waxed paper or aluminum foil is used for the packaging of the gum.
Additional paper sleeves can also be used. Chewing gum can be molded in pellet form. The
blister packing is generally used with the cardboard band around it. Cellophane blister full wrap
with tear thread is also used. Individual sticks are packed in aluminum foil and resealable carton
(http://www.loeschpack.com) .

( a. ) (b)

78
 (c) (d)

(f)
(e)

(g)

79
Figure 7.1: Typesof chewing gum a) , (b) Stick and Tabs, c) Pellets and Pillows gum, d)
Hollow ball gums, e) Liquid -filled gum, f) Gum- filled candy and g) Compressed gum

7.2 REGULATORY PERSPECTIVE OF MEDICATED CHEWING GUM

Due to the chewing gum's gummy nature, it cannot be analyzed by the dissolution apparatus used
for tablets or capsules. Since medicated chewing gum is a chewable dosage form, thus in -vitro
estimation of the gum's drug release is a restraining stage in its development. Therefore a need
has been felt for developing in vitro drug release apparatus and standard evaluation methods. As
medicated chewing gum is a single dose formulation, it must comply with the test for content
uniformity and weight variation. Besides, microbial testing has to be certified. The European
Pharmacopoeia is the leading authority that regulates the in- vitro release testing for medicated
chewing gums using two official devices. Release testing is prescribed to control the
bioavailability of drugs. The United States Pharmacopeia has not officially adopted a release test
for chewing gum, but it has provided specific monographs for nicotine polacrilex gums with
evaluation tests such as identification, assay, content, and mass homogeneity (Haghbani et al.,
2018). Usually, in Australia, chewing gums are regulated as foods except for extremely sought
out products such as smoking termination gums or dental remineralization products. Various
Factors that boost the development of medicated chewing gums globally are large demographic
dependence on smoking, including men and women, and enhanced increase in alertness about
dental cleanliness. The global medicated chewing gums market is found in Europe, Latin
America, North America, Middle East & Africa, and the Asia Pacific. Due to the extension of
nicotine gum research and neutraceutical enterprises in Germany, France, and the U.K., Europe
has become the key player in the field of medicated chewing gums. The medicated chewing
gums marketplace in Europe is predictable to inflate at a speedy pace. The medicated chewing
gums are prevalent in the Asia Pacific due to a large population relying on medicated gums,
numerous active pharmaceutical ingredient (API) manufacturers, and growing dental healthcare.
Additionally, an escalation in the government roles for smoking termination is predicted to
develop the market in evolving economies like China and India
(https://www.transparencymarketresearch.com/medicated-chewing-gumsmarke.html).
Various regulations related to medicated chewing gum are described below.

80
7.2.1 USA
The medicated chewing gums should be manufactured under cGMP and GRAS (generally
regarded as safe) guidelines. These regulations are given by the Food & Drug Administration
(FDA) under title 21 CFR section 172.615. This guideline described the quantity used and safety
specifications for food additives used in chewing gums. In the case of masticatory substances
(gum base), various natural and synthetic gums are described based on their family, molecular
weight, etc. The plasticizing materials or softeners (glycerol esters) have been specified based on
the acid number. The antioxidants should be used within a limit of 0.1%. To guarantee the safe
use of the additive, the label of the food additive should bear the name of the additives
(https://www.accessd ata.fda.gov/scripts/cd rh/cfdocs/cfcfr/CFRSearch.cfm?fr=172.615). As
USP does not contain an official in-vitro dissolution apparatus for medicated chewing gums,
drug product manufacturers can develop their in-house apparatus for dissolution testing.
7.2.2 EUROPE
The European Pharmacopeia has established in- vitro dissolution testing of medicated chewing
gums to test the drug released during chewing. It published its first monograph on medicated
chewing gum in 1998. But there are no global standards to evaluate controlled release tests in
medicated gums (Rider et al., 1992). The official monographs were extended by the European
Pharmacopeia in 2000 to define the manufacturing methods and improved in vitro dissolution
apparatus of chewing gums concisely and precisely. The Ph. Eur in 8th edition described
devices, A and B, for evaluating the in vitro release of actives from chewing gums (European
Pharmacopeia, 2014). Christrup and Moller designed the official apparatus A. It helps in
predicting the drug release mechanism from the gum, thus deriving the in -vivo in- vitro
correlations (Christrup et al., 1986). Another chewing gum release apparatus (B) includes some
additional features such as temperature control, twisting angle and jaw distance control, etc.
which was later recommended (Kvist et al., 2000). The drug release mechanism can also be
studied by using various in- vivo techniques such as chew- out studies, salivary and urinary
studies, which involves human volunteers. Then the chewed gum is analyzed using U.V.
spectroscopy. Pharmacopoeial quality tests are essential to guarantee the product's
biopharmaceutical quality (Gajendran et al., 2012). The detailed account of the in-vitro
dissolution machine has been given in chapter-6. The European Union is the hub for developing
medicated chewing gums. Several companies in Europe are engaged in the full-scale production

81
of medicated chewing gums. The steps followed in the manufacturing of chewing gums require
various regulatory parameters and timelines, which are described in Figure 7.2.
(www.alkalon.com).al.
7.2.3 AUSTRALIA
Food Standards Australia New Zealand (FSANZ) has an explicit food quality for chewing gum,
which only permits for the use of calcium to some chewing gums. There is uncertainty regarding
chewing gums regulated as foods or therapeutic goods. Also, there is an ambiguity about whether
chewing gum delivers the active component systemically or not as there is no evidence. The
dosage form of chewing gum in Australia is considered at the food/medicine frontier and is
precisely cited under the definition of food (www.tga.gov.au).

Contract research for various

companies

Pilot scale formulation development

& Analytical testing including
stability , bioequivalent studies
Management of regulatory dossiers
for worldwide submissions via MRP
or national procedures.

Scale up manufacturing & product

release in the form of bulk packs
Figure 7.2: Stages of chewing gum development in Europe
7.2.4 INDIA
The chewing gum, patches, and inhalers with nicotine content are controlled as drugs under the
Drugs and Cosmetics Rules (DCR). The Drug Controller General of India (DCGI) has certainly
approved nicotine chewing gums (2 mg and 4 mg). Besides, there is no obligation for a drug-
selling license to vend this formulation (https://www.fdli.org/2019/05/spotlight-on-tobacco-
reduced-risk-tobacco-products-a-case-of-policy-vacuum-in-india/). To date, there are no
regulatory guidelines regarding the manufacturing, testing, and evaluation of medicated chewing

82
gums in India. The chewing gums are manufactured and evaluated on the basis of guidelines
issued by the European Pharmacopoeia and USFDA. The research and novelty are some of the
vital factors accountable for the development of health care skills. For example, biodegradable
chewing gum of Diphenhydramine for motion sickness was developed using corn- zein as a gum
former by the School of Pharmaceutical and Sciences, RGPV, Bhopal (Mehta et al., 2014).
Aizant, a contract manufacturing organization (CRO) company in India, working on behalf of
Enorama Pharma, is a key player in developing medicated chewing gums in India. The main
companies in the global Medicated Chewing Gums market are Skyepharma Production SAS,
Fertin Pharma, Alkalon A/S, ENORAMA PHARMA AB, GlaxoSmithKline, Mastix LLC,
Omega Pharma Ltd, Agro Gums, WM. Wrigley Jr. Company, Perfetti Van Melle etc.
(https://www.transparencymarketresearch.com/medicated-chewing-gumsmarke.html).
Zenara Pharmaceuticals in Telangana is involved in the development and commercialization of
Nicotine Chewing Gums and Lozenges for smoking cessation (https://www.indiamart.com/
zenara-pharma-private-limited/other-products.html#nicotinereplacement). Fertin India
Private Limited opened the first medicated chewing gum industrial plant in India in 2015 in Goa.
The main products are Nicotine Replacement Therapy (NRT) medicated gums for smoking
cessation. Fertin India has alliance with companies like GSK, Novartis, and Perrigo
(http://www.pharmabiz.com/NewsDetails.aspx?a id=91189&sid=1). Nicotine gums have
been manufactured by Cipla Healthcare limited, India, under the brand name Nicotex (2mg,
4mg).

References
1. Hagbani, T.A., Nazzal, S. (2018). Medicated Chewing Gums (MCGs): Composition,
Production, and Mechanical Testing. AAPS Pharm Sci Tech.., 19(7): 2908-2920.
2. Pagare, P. K., Satpute, C. S., Jadhav, V. M. & Kadam, V. (2012). Medicated chewing
gum:
A novel drug delivery system. J. App. Pharm. Sci., 2:40-54.
3. Kinjal R. Shah, Tejal A. Mehta. 2014. Medicated Chewing Gum- A Mobile Oral Drug
Delivery System, IJPRIF., 6(1): 35-48.
4. http://www.cafosa .com/EN_Different_types_of_chewing_gum .
5. http://www.loeschpack.com.

83
6. Pharmacopoeia E. General monograph on dissolution test for medicated chewing gums.
European directorate for the quality of medicines. 8th Ed: Council of Europe; 2014. p.
325.
7. Gajendran J, Kraemer J, Langguth P. (2012) .In vivo predictive release methods for
mediccated chewing gums. Biopharm. Drug. Dispos; 33(7):417–24.
8. Kvist C, Andersson SB, Fors S, Wennergren B, Berglund J. (1999).Apparatus for studying
in vitro drug release from medicated chewing gums. Int. J. Pharm.; 189 (1):57–65.
9. Christrup LL, Moeller N. (1986).Chewing gum as a drug delivery system. In vitro
simulation of human mastication and influence of formulation upon the release of a water-
soluble drug. Arch. Pharm. Chem. Sci; 14: 30–36.
10. Rider., J.N, Brunson, E.L, Chambliss, WG. (1992).Development and evaluation of a novel
dissolution apparatus for medicated chewing gum products. Pharm. Re.s ; 9: 255–259.
11. www.alkalon.com.
12. www.tga.gov.au.
13. https://www.transparencymarketresearch.com/medicated-chewing-gums-marke.html.
14. Mehta, F, Trivedi, P. (2014). Formulation and Characterization of Biodegradable
Medicated Chewing Gum Delivery System for Motion Sickness using Corn Zein as Gum
Former. Trop. J. Pharm. Res., 14(5): 753-760.
15. https://www.indiamart.com/zenara-pharma-private-limited/other-products.html#nicotine-
replacement.
16. http://www.pharmabiz.com/NewsDetails.aspx?aid=91189&sid=1.
17. https://www.fdli.org/2019/05/spotlight-on-tobacco-reduced-risk-tobacco-products-a-case-
of-policy-vacuum-in-india/.

84
 CHAPTER 8
CONCLUSION
The oral route of drug delivery is the supreme of all routes as it provides easy administration and
patient conformity. Medicated Chewing Gum (MCG) is an innovative drug delivery system that
provides both elegance and therapeutic benefits. The drug release mechanism from MCG
involves the release of active constituent in saliva after chewing, which can be available for
either local absorption or for systemic absorption via GIT. Medicated Chewing gum has been
exploited for various medications such as Nicotine, Dextromethorphan Hydrobromide, Antacids,
Cetirizine, Miconazole, Dimenhydrinate hydrochloride, Aspirin, Ondansetron Hydrochloride,
Caffeine, Antimicrobial decapeptide, and Nystatin, etc. The formulation & manufacturing
methods are summarized, which dictate the quality & texture of medicated chewing gums. MCG
is a combination of masticatory resins with active ingredients, sweeteners, flavors, plasticizers,
fillers, etc. Cyclodextrin complexation, ion exchange resins, lipids, microencapsulation,
solubilizing agents, buffering agents are some of the formulation techniques that may alter the
taste, aqueous solubility, and release profile of the drug. Various methods are used for the
production of MCG, including the melting method, cooling-grinding method, and direct
compression method. One of the most palatable oral dosage forms is taste-masked medicated
chewing gum, which can provide both health & nutrition with an elegancy. A number of patents
and technological developments have been made in the development of more palatable and
acceptable dosage form. Innumerable commercial patented technologies platforms such as
Medichew®, Rev-7®, Pharmagum®, Health in Gum®, are described which accelerate the
manufacturing process by providing a ready to mix directly compressible technology. MCG’s
can be evaluated by using various official & non–official tests described by European
Pharmacopoeia. Content uniformity, weight variation, in- vitro drug release, in vivo salivary and
urinary studies, ex vivo buccal permeation studies are some of them. Medicated chewing gums
can be a great platform as a drug delivery system to provide a better patient compliance and
efficacy in the near future.

85
 List of Contributors
Prerna Kaushik
Research Scholar, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak (Haryana), India-124001
E-mail:- pkaushik184@gmail.com
Deepak Kaushik
Assistant Professor, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak (Haryana), India-124001
E-mail:- deepkaushik1977@gmail.com
Pankaj Kumar
Pharmacovigilance Scientist, Wipro Pvt. Ltd, Sarita Vihar, New Delhi, India.
E-mail- pankaj.jangra888@gmail.com.
Vineet Mittal
Assistant Professor, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak (Haryana), India-124001
E-mail:- vineetmpharma@gmail.com
Md. Habibur Rahman
Department of Pharmacy, Southeast University, Banani, Dhaka-1213, Bangladesh.
Deepika Purohit
Assistant Professor, Department of Pharmaceutical Sciences, Indira Gandhi University,
Meerpur, Rewari, India
E-mail:- deeps.msip12@gmail.com
Parijat Pandey
Assistant Professor, Shri Baba Mastnath Institute of Pharmaceutical Sciences and
Research, Baba Mastnath University, Rohtak (Haryana), India – 124001
E-mail:- parijatpandey98@gmail.com
Ravinder Verma
Research Scholar, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak (Haryana), India-124001
E-mail:- ravinderbasniwal7661@gmail.com
Ritu Kaushik

86
Research Scholar, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak (Haryana), India-124001
E-mail:- ritusharmamdu12@gmail.com
Vandana Singh
Research Scholar, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak (Haryana), India-124001
E-mail:- vandanasingh2212@gmail.com

87
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