INTRODUCTION:

We are considering here, more precisely, the oral mucosal drug delivery system as we have to be acquainted with only the absorption of the active drug from the gum via the mucosal membrane of the buccal cavity.

The main area of challenge and the main aim for the design of such an oral mucosal drug delivery system is to simply bypass or minimize the first-pass effect of the liver. It is known that if a drug is of a controlled or the sustained type, and if it is administered via the oral route, then very less therapeutic effect of the drug is seen due to the hepatic effect. To explain in short, the oral drug delivery is of buccal and sublingual type and the drug through these routes, after absorption, is passed into the reticulate vein underneath the oral mucosa, then through the facial veins, internal jugular vein, braciocephalic vein and then into the systemic circulation. This whole pathway plays an important role so as to bypass the first pass effect of the liver. Sublingual absorption is rapid in action but is of short duration, while the buccal route is not only rapid in action but it also shows prolonged retention of the drug action. Thus, we can say that the oral mucosa is the centre for the absorption of the drug for the controlled and sustained type forms.

Fig 1: Medicated chewing gum

Fig 2: MCG as drug delivery system

The chewing gum may be gaining momentum now-a-days on a large scale but it is an older concept of drug delivery. This is because; the first chewing gum of its kind was manufactured some 150-175 years ago. Ancient man also used different kind of roots, leaves, even barks of trees for cleaning of teeth and as a breath freshener. The world war was also enhanced the use of chewing gum, as for the soldiers who were at the warfront and could easily chew the portable gum to clean teeth and breathe freshening. The chewing gum was first introduced to pharmacy when the aspirin containing gum was manufactured in 1928, but the sales of such gum went high when they were introduced in 1978. From then, the gum containing dosage forms have been used on a very large scale for the various disorders of the buccal cavity, gingivitis and caries. The fluorine gums are mostly used for this.

Pharmacological active agents or drugs are formulated into variety of dosage forms like tablets, capsules, injectables, inhalers, ointments etc considering physicochemical properties, pharmacokinetic and Pharmacodynamics parameters and biopharmaceutical aspects of drugs. In addition to its confectionary role, chewing gum (cg) also has proven value as a delivery vehicle for pharmaceutical and nutraceutical ingredients. Today cg is convenient drug delivery system which is appropriate for a wide range of active substances. Many therapeutic agents are absorbed in the oral cavity. For the drugs having significant buccal absorption, dosage forms such as lozenges, chewable tablets and chewing gum permits more rapid therapeutic action compared to per-oral dosage forms. Chewable tablets and chewing gum have been very well received by the parents for use in children with full dentition. Children in particular may consider chewing gum as a more preferred method of drug administration compared with oral liquids and tablets. The use of mcg is feasible in local treatment of diseases of oral cavity as well as treatment of systemic conditions.

Medicated Chewing Gum:-^{[1, 2]}

Definition:-

“Medicated chewing gum is solid, single-dose preparations that have to be chewed and not swallowed; chewing gums contain one or more active ingredient that is released by chewing”.

“A medicated chewing gum is intended to be chewed for a certain period of time, required to deliver the dose, after which the remaining mass is discarded”.

Medicated chewing gum is considered a valid drug delivery system that releases the active ingredient by chewing. Medicated chewing gum offers a wide range of advantages that make it an excellent alternative. Chewing gum has been proven as a great delivery vehicle for nutrients and drugs. For example, nicotine smoking cessation chewing gum is one of the most successful controlled-release drugs.

Then there are the benefits of chewing gum in general; the most significant one is that of oral care. Chewing sugar-free gum after eating is clinically proven to be an important part of good oral health. There are many studies that demonstrate that chewing gum stimulates saliva flow and increases plaque ph, which prevents tooth decay. Moreover, chewing gum increases alertness and concentration, helps to control weight management and reduces stress.

Added to the therapeutic effect of the drug there is a very positive synergistic effect brought on by the action of chewing, which has a positive effect on the patient’s compliance. Cafosa sees a strong potential for medicated chewing gum as an innovative and valid alternative to standard, chewable or orally disintegrating tablet presentations. Recently as a part of “a taste for bold ideas”, the bill and melinda gates foundation gave grants to encourage creativity among scientists, especially on those areas that have never been focused on health before.

Formulation of MCGS:-^{[1,2,3,13,14]}

Chewing gum is a mixture of natural or synthetic gums and resins, sweetened with sugar, corn syrup, artificial sweetners and may also contain coloring agents and flavor. The basic raw material for all cg is natural gum chicle, obtained from the sapodilla tree. Chicle is very expensive and difficult to procure therefore other natural gum or synthetic materials like polyvinylacetate and similar polymers can be used as gum base.

Typically Chewing Gum comprises two parts:

1 Water insoluble chewable gum base portion.

2 Water-soluble bulk portion.

Some Important Formulation Aspect:-^[1,2,13,14]

1) Increased amount of softners and emulsifiers in gum base fasten release whereas hard gum may retard.

2) Cyclodextrin complexation or solubilisation technique increases aqueous solubility of drugs that are poorly water soluble.

3) A solid system of lipophilic active ingredients bound to the cation exchange resin permits a sustained drug delivery system.

4) Microencapsulation or agglomerations are the methods to modify and control the release of active ingredient.

Factors affecting release of active ingredient:^[1,2,13,14]

1) Contact Time:

The local or systemic effect is dependent on time of contact of MCG in oral cavity. In clinical trial chewing time of 30 minutes was considered close to ordinary use.

2) Physicochemical properties of active ingredient:

Physicochemical properties of active ingredient plays very important role inrelease of drug from MCG. The saliva soluble ingredients will be immediately released within few minutes whereas lipid soluble drugs are released first into the gum base and then released slowly.

3) Inter individual variability:

The chewing frequency and chewing intensity which affect the drug release from MCG may vary from person to person. In-vitro study prescribed by European Pharmacopoeia suggest 60 cycles per minute chewing rate for proper release ofactive ingredient.

4) Formulation factor:

Composition and amount of gum base affect rate of release of active ingredient. If lipophilic fraction of gum is increased, the release rate is decreased.

Manufacturing processes:^[1,2,13,14]

Different methods employed for the manufacturing of CG can be broadly classified into three main classes namely.

1 Conventional/ traditional Method (Melting).

2 Freezing, grinding and tabletting Method.

3.Direct Compression Method

1. Conventional/ traditional Method:

Components of gumbase are softened or melted and placed in a kettle mixer to which sweetners, syrups, active ingredients and other excipients are added at a definte time. The gum is then sent through a series of rollers that form into a thin, wide ribbon. During this process, a light coating of finely powdered sugar or sugar substitutes is added to keep the gum away from sticking and to enhance the flavour. In a carefully controlled room, the gum is cooled for upto 48 hours. This allows the gum to set properly. Finally the gum is cut to the desired size and cooled at a carefully controlled temperature and humidity.

Limitations:

1) Elevated temperature used in melting restricts the use of this method for thermo labile drugs.

2) Melting and mixing of highly viscous gum mass makes controlling of accuracy and uniformity of drug dose difficult.

3) Lack of precise form, shape or weight of dosage form.

4) Technology not so easily adaptable to incorporate the stringent manufacturing conditions required for production of pharmaceutical products.

5) Such a chewing gum composition is difficult to form into chewing gum tablets because of their moisture content (2-8%). If attempted to grind and tablet such a composition would jam the grinding machine, stick to blades, screens adhere to punches and would be difficult to compress.

2. Cooling, Grinding and Tabletting Method:

This method has been developed with an attempt to lower the moisture content and alleviate the problems mentioned in conventional method.

Cooling and Grinding:

The CG composition (base) is cooled to a temperature at which the composition is sufficiently brittle and would remain brittle during the subsequent grinding step without adhesion to the grinding apparatus.The temperature required for cooling is determined in part by the composition of the CG and is easily determined empirically by observing the properties of the cooled chewing gum composition. Generally the temperatures of the refrigerated mixture are around -15oC or lower. Amongst the various coolants like liquid nitrogen, hydrocarbon slush use of solid carbon dioxide is preferred as it can give temperatures as low as -78.5oC, it sublimes readily on warming the mixture, is not absorbed by the chewing gum composition, does not interact adversely with the processing apparatus and does not leave behind any residue which may be undesirable or potentially hazardous.

The refrigerated composition is then crushed or ground to obtain minute fragments of finely ground pieces of the composition. Alternatively, the steps of cooling the chewing gum composition can be combined into a single step. As an example, cooling the grinding apparatus itself which can be done by contacting the grinding apparatus with a coolant or by placing the grinding apparatus in a cooling jacket of liquid nitrogen or other cold liquid. For more efficient cooling, the chewing gum composition can be pre cooled prior to cooling to the refrigeration temperature. Sometimes a mixture of chewing gum composition, solid carbon dioxide and precipitated silica is ground in a mill grinder in a first grinding step. Additional solid carbon dioxide and silica are added to the ground composition, and the composition is further ground in a second grinding step. This two step grinding process advantageously keeps the chewing gum composition at a very low temperature. The presence of solid carbon dioxide also serves to enhance the efficiency of the grinding process.

Use of anti-caking agent:

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

Tabletting:

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

3.Use of directly compressible chewing gum excipients:

The manufacturing process can be accelerated if a directly compressible chewing gum excipient is available. The limitations of melting and freezing can be overcome by the use of these. PHARMAGUM®, is one such compactable gum system developed by SPI Pharma. Pharmagum is a mixture of polyol and or sugars with a chewing gum base. It is available as directly compressible powder, free flowing powder which can be compacted into a gum tablet using conventional tablet press thus enabling rapid and low cost development of a gum delivery system. It is manufactured under CGMP conditions and complies with Food Chemicals Codex specifications as well as with FDA, so they can be considered as "Generally regarded as safe" (GRAS). Pharmagum® is available in three forms namely S, M and C. Pharmagum® M has 50% greater gum base compared to Pharmagum. Pharmagum consists primarily of gumbase and sorbitol. Pharmagum contains gumbase, mannitol and is malt. Release of nicotine from directly compressible nicotine gum formulations and from Nicorette prepared by conventional methods has shown that use of Pharmagum in formulation showed a faster release rate.

Fig 4: Single-module chewing apparatus from Wennergren.

Investigations of the performance of the chewing apparatus with multiple drug products were published by Wennergren. The influences of different operational parameters of the chewing gum apparatus on drug release have been carefully investigated.

Quality control evaluation tests^[1,2,4]

In-vitro drug release testing apparatus:

Number of apparatus for studying in-vitro drug release from medicated chewing gum has been developed. An apparatus for in vitro drug release testing of medicated chewing gums has been developed by Kvist C. They have studied the effect chewing surfaces, twisting movements of surfaces and temperature of test medium on release rate of drug from MCG. Another novel dissolution apparatus has been developed for MCG by Rider JN. The apparatus consist of conical Teflon base and a rotating, ribbed Teflon plunger suspended in a dissolution vessel. The rotation speed, plunger frequency, medium volume, medium type, medium sampling location, number of plunger ribs and number of gum pieces were studied by them.

The temperature of the chamber can be maintained at 37±0.5°C and the chew rate can be varied. Other adjustable settings include the volume of the medium, the distance between the jaws and the twisting movement. The European Pharmacopoeia recommends using 20 ml of unspecified buffer (with a pH close to 6) in a chewing chamber of 40 ml and a chew rate of 60 strokes per minute.

Drug Release Testing Methodology^[3,4]:

Ph. Eur. has adopted an apparatus to determine the release rate from chewing gums formulations. The basic principle is a simple masticatory movement employed to simulate the chewing action on a piece of gum placed in a small chewing chamber containing a known volume of buffer solution at a given temperature. The drug release rate is influenced by the chewing rate and angle, which provides the necessary shear force to expose new gum surfaces and is a requisite for further drug release.

The mechanism and kinetics of drug release from chewing gums have not yet been completely understood due to the complexity of the formulation itself. The transition from the inactive gum to the active dosage form is influenced by

· mechanical forces

· temperature

· wettability and water permeation.

As a general rule, under sink conditions, the rate at which the drug is released is directly proportional to the chewing frequency and aqueous solubility of drug substance and is indirectly proportional to the mass of the gum base.

Applications:

1) Dental caries^[2,3]

a. Prevention and cure of oral disease are targets for chewing gum formulations.

b. It can control the release rate of active substances providing a prolonged local effect.

c. It also re-elevates plaque pH which lowers intensity and frequency of dental caries.

d. Fluoride containing gums have been useful in preventing dental caries in children and in adults with xerostomia.

e. Chlorhexidine chewing gum can be used to treat gingivitis, periodontitis, oral and pharyngeal infections.

f. It can also be used for inhibition of plaque growth.

g. Chlorhexidine chewing gum offers numerous flexibility in its formulation as it gives less staining of the teeth and is distributed evenly in the oral cavity.

h. The bitter taste of chlorhexidine can be masked quite well in a chewing gum formulation.

2.) Systemic therapy:^[9,10,11,12]

Chewing gum as a drug delivery system is beneficial to a number of indications, some of which are discussed below:

(a) Pain:

Treatment of minor pains, headache, muscular aches can be successfully accomplished.

(b) Smoking cessation:

Chewing gum formulation containing nicotine, lobeline and silver acetate have been clinically tested as aids to smoking cessation. Nicotineis a natural alkaloid occurring in the leaves of tobacco plant. It is a therapeutic agent intended to help smokers break the psychological habit of smoking by reducing the nicotine withdrawal symptoms normally experienced when smoking is stopped. The formulation nicoretteo available as mint and classic with different flavor and dosage, is developed with ion- exchange resin, released 90% of drug after 30 min chewing. The release rate was controlled by the rate and vigour of chewing. Thus the patient can control the drug intake to match his needs. Increasing the pH of the medium in which it is dissolved can enhance nicotine absorption.

(c) Obesity:^[5,8]

Active substances like chromium, guaran and caffeine are proved to be efficient in treating obesity. Chromium is claimed to reduce craving for food due to an improved =blood-glucose balance. Caffeine and guaran stimulate lipolysis and have a thermogenic effect (increased energy expenditure) and reduce feeling of hunger.

(d)Other indications:^[7]

Xerostomia, Allergy, Motion sickness, Acidity, Cold and Cough, Diabetes, Anxiety etc are all indications for which chewing gum as drug delivery system could be beneficial.

Other Novel Pharmaceutical Applications: - ^[5,9,10]

i) Chewing gum for dental caries, plaque problems and as a breath freshener is commonly prescribed by dentists.

ii) For other problems related to oral infections, the chewing gum is used. The best example is that of Chlorohexidine, which is commonly used for dental disorders, has a bitter taste and this can be easily masked by using the chewing gum form of the active drug. The gum form is said to be more effective than the mouthwash or the gargle type of dosages.

iii) Benzoin has a great importance in curing the throat and bronchial inflammation. Hence, new drug designs involving Benzoin are to be designed to utilize the soothing and expectorant action of Benzoin in case of Laryngitis.

iv) The common alkaloid opium, having a considerable Morphine content is used in cases of the throat, gastric and diarrhoeal problems. Here, too, novel drug designs are needed to give an analgesic and narcotic effect. Also, it can act as an anti-peristaltic agent and so is useful in conditions like diarrhoea, dysentery and dyspepsia. As it has a bitter taste, so the gum form can be best suited for administration.

v) Chewing gum can also be used for the easy administration of antacids. The
Aspirin Chewing Gum is known to exert its analgesic effect. It should be noted that the gum form of Aspirin is even more effective than its tablet form.

vi) Other than this, the drugs that are to be prevented from the hepatic first-pass effect can be viewed to be designed in the form of gum, considering the physical, chemical and pharmacological properties if the active drug.

Therapeutic Uses of MCG:^[4,6,7]

The use of sugar free gum to counteract dental caries by stimulation of saliva secretion has led to a more widespread use and acceptance of gums. It has been proved that chewing nonmedicated chewing gums increases plaque pH, stimulates saliva flow and decrease decay. MCGs containing Chlorhexidine for treatment of gingivitis and plaque has been available. The use of MCG in the treatment of oral infections has also been reported. The active ingredient is released from the MCG and sufficient concentration is achieved in the oral cavity to prevent or treat local conditions of oral cavity. CG is also useful delivery system for agents intended for systemic delivery. Drug that is released from gum within oral cavity can be absorbed via buccal mucosa. The MCGs can also be used as an alternative tool to buccal and sublingual tablets which are intended to act systemically because active ingredient is released more uniformly and cover greater area of absorption in oral cavity. Oral diseases are prevented or cured with MCG. MCGs for systemic effect in conditions like vitamin C deficiency, pain and fever, alertness, motion sickness, smoking cessation, as well as for local effect in the conditions like plaque acid neutralization, fresh breath, disinfection, anti-caries, antiplaque, antifunga, antibacteria are available.

ADVANTAGES OF MCGS:^[1,2,6]

1 Dose not requires water to swallow. Hence can be take anywhere.

2 Advantageous for patients having difficulty in swallowing.

3 Excellent for acute medication.

4 Counteracts dry mouth, prevents candidacies and caries.

5 Highly acceptable by youngsters.

6 Avoids First Pass Metabolism and thus increases the bioavailability of drugs.

7 Fast onset due to rapid release of active ingredients in buccal cavity and subsequent absorption in systemic circulation.

8 Gum does not reach the stomach. Hence G.I.T. suffers less from the effects of excipients.

9 Stomach does not suffer from direct contact with high concentrations of active principles, thus reducing the risk of intolerance of gastric mucosa

10 Fraction of product reaching the stomach is conveyed by saliva delivered continuously and regularly. Duration of action is increased.

11 Aspirin, Dimenhydrinate and Caffeine shows faster absorption through MCG than tablets.

Disadvantages of MCGS:^[1,2,6]

1 Risk of over dosage with MCG compared with chewable tablets or lozenges that can be consumed in a considerable number and within much shorter period of time.

2 Sorbitol present in MCG formulation may cause flatulence, diarrhea.

3 Additives in gum like flavoring agent, Cinnamon can cause ulcers in oral cavity and Licorice cause Hypertension.

4 Chlorhexidine oromucosal application is limited to short term use because of its unpleasant taste and staining properties to teeth and tongue.

5 Chewing gum has been shown to adhere to different degrees to enamel dentures and fillers.

6 Prolong chewing on gum may result in pain in facial muscles and earache in children.

Limitations of Chewing gum as Drug Delivery System:^[1,2,5]

Chewing gum has several disadvantages as the drug released into saliva disappears rapidly from the oral cavity because of involuntary swallowing. The concentration of drug in the oral cavity always tends to decrease as a result of salivary dilution. Drug release from chewable formulations has shown to be strongly influenced by the way patient chews the formulation. Administration of such dosage form is restricted to short period of time because the presence of the delivery system in the oral cavity causes disturbance in drinking, eating and speaking. Despite these limitations, chewing gum formulation affords extended delivery period compared to solution and fast dissolving tablets.

ADVERSE EFFECTS:

The nicotine gum is not to be used in pregnancy and breast feeding because nicotine is detectable in breast milk. Also, nicotine gum is not recommended in peptic ulcers, stomach problems, angina pectoris, chest pains, other heart problems, diabetes. The nicotine gum is to be taken under advice in case when other medicines are used and if some allergies are seen. The dose is different for different people even if they show similar symptoms. Generally, side-effects of this gum are not seen but some people may be allergic or sensitive to the gum constituents and may produce rash or irritation in throat, tongue or oral cavity. The nicotine chewing gum cannot be used by non-smokers and people under 18 years. Also, people should not use the gum and smoke simultaneously. Counseling may help the patients to quit smoking. Doses of nicotine that can be tolerated by adults may produce severe effects in small children and may lead to fatal poisoning. When tested in animals, Nicotine has shown non-specific retardation of foetal growth, decreased fertility, prolonged pregnancy etc. The carcinogenicity of tobacco is due to the formation of pyrolysis products. Administration of the nicotine chewing gum prevents the formation of these products.

OVERDOSE:

Overdose of nicotine is rare and can be seen only in very few people. But even a small dose may be fatal for children and can lead to poisoning. Since the release of nicotine is slow, very less nicotine is absorbed from stomach and intestine and if any present, is inactivated by liver. If overdose or poisoning is seen, administration of salt water should be done, activated charcoal can also be used and gastric lavage should be carried out.

FUTURE TRENDS:^[1,2,4,6]

Chewing gum not only offers clinical benefits but also is an attractive, discrete and efficient drug delivery system. A few decades ago, the only treatment for some disease was surgical procedure but now more and more disease can be treated with Novel Drug Delivery Systems.

Cafosa has developed a new excipient, Health in Gum — a directly compressible powder gum containing a mix of ingredients to which APIs can be added. To date, Health in Gum is being used by customers as a way to differentiate their products in a very competitive market and to provide added value to consumers.

Governments and healthcare payers are continually demanding cheaper medicines. While it is true that cheaper medicines are needed to reduce treatment costs, medicines still need to be effective and safe. In this sense, novel drug delivery technologies will continue to be developed, providing both innovation for end users and market differentiation for the companies. Medicated chewing gum is a valid alternative to standard, chewable or orally disintegrating tablet presentations.

CONCLUSION^[1,2]:

· Newest system with potential uses in pharmaceuticals.

· The drug intended to act in oral cavity often have low water and saliva solubility and MCG’S constitute valuable delivery systems for such drugs.

· Acceptance of MCG’S is increasing day by day.

REFERENCES:

1. Drug-interactions.com [homepage on the Internet]. Indianapolis: Indiana University Department of Medicine; 2003 [updated 17 May 2006; cited 30 May 2006]. Available from: http://medicine.iupui.edu/flockhart/

2. Milgrom P, Ly KA, Roberts MC, Rothen M, Mueller G, Yamaguchi DK (2006). "Mutans streptococci dose response to xylitol chewing gum". Journal of Dental Research85 (2): 177–181. doi:10.1177/154405910608500212. PMC2225984. PMID16434738.

3. Schaeken MJ, van der Hoeven JS (1993). "Control of calculus formation by a dentifrice containing calcium lactate". Caries Research27 (4): 277–279. doi:10.1159/000261550. PMID8402801.

4. "Substance found in chewing gum could be labelled toxic". Canada.com. 2008-05-30. http://www.canada.com/topics/bodyandhealth/story.html?id=06e fd58-ebb9-4bd3-b239-d0f87b743155. Retrieved 2012-01-25.

5. www.ventanabiotech.com/news/132/combating-obesity-with-appetite-suppressing-chewing-gum

6. www.johnisfit.com/2007/10/02/the-benefits-of-chewing-gum/

7. www.evenfallneedleworks.com/tag/chewing-gum

8. www.theproteinreview.com/2009/07/chewing-gum-to-lose-weight

9. www.ehow.com/about_5421282_chewing-gum-helps-stop-smoking.html

10. wiki.answers.com/Q/Can_chewing_gum_get_rid_of_smoking_habits

11. www.quit-smoking-cigarettes-now.com/260/nicorette-nicotine-polacrilex-chewing-gum-2-mg-stop-s...

12. www.healthcaremagic.com/community/Smoking-Alcohol-and-Other-Addictions/side-effects-of-tobacc...

13. Kashket S, Yaskell T (1997). "Effectiveness of calcium lactate added to food in reducing intraoral demineralization of enamel". Caries Research31 (6): 429–433. doi:10.1159/000262434. PMID9353582

14. Suda R, Suzuki T, Takiguchi R, Egawa K, Sano T, Hasegawa K (2006). "The effect of adding calcium lactate to xylitol chewing gum on remineralization of enamel lesions". Caries Research40 (1): 43–46. doi:10.1159/000088905. PMID16352880.

Received on 25.03.2015 Modified on 11.04.2015

Res. J. Pharm. Dosage Form. & Tech. 7(3): July-Sept., 2015; Page 232-240

DOI: 10.5958/0975-4377.2015.00034.8

Component	Function	Example
Elastomers	Provides elasticity and controls gummy texture	Natural (chicle gum, nispero, rosadinha, jelutong,periollo, lechi-capsi, sorva etc.) and synthetic rub- bers (butadiene, styrene copolymers, polyisobutylene, polyethylene mixtures, polyvinylalcohol etc.)
Elastomer solvents	Softening the elastomer base component	Terpinene resins (polymers of alpha-pinene or beta-pinene), modified resins or gums (hydrogenated, dimerized or polymerized resins)
Plasticizers	To obtain a variety of desirable textures and consistency proper-ties	Lanolin, palmitic acid, oleic acid, stearic acid, gly-ceryl triacetate, propylene glycol monostearate, glycerine, natural and synthetic waxes, hydroge-nated vegetable oils, paraffin waxes, fatty waxes, sorbital monostearate, propylene glycol
Fillers or texturizers or mineral adjuvant	Provide texture, improve chewa- bility, provide reasonable size of the gum lump with low dose drug	Calcium carbonate, magnesium carbonate, alumi-num hydroxide, talc, aluminum silicate

Component	Function	Example
Softeners and emulsifiers	These are added to the chewing gum in order to optimize the chewability and mouth feel of the gum	Glycerine, lecithin, tallow, hydrogenated tallow,mono/ di/ tri- glycerides
Colorants and whiteners	Gives the formulation soothing color and improves acceptability of the formulation	Titanium dioxide, natural food colors and dyes suit-able for food, drug and cosmetic applications
Sweeteners	To provide the desired sweetness of the product Water soluble sweetening agents (xylose, ribulose, glucose, mannose, galactose, sucrose, fructose, mal-tose, monellin, sugar alcohols like sorbitol, mannitol etc.),	water soluble artificial sweeteners (sodium or calcium saccharin salts, cyclamate salts etc.), di-peptide based sweeteners (aspartame, alitame etc.), naturally occurring water soluble sweeteners, chlo-rinated derivatives of ordinary sugar (sucralose),protein based sweeteners (thaumatin I and II)
Antioxidants	Prevents any possible microbial growth	Butylated hydroxyl toluene, butylated hydroxyani-sole, propyl gallate

Manufacturing Methods	Limitation
Conventional/ traditional method	Manufacturing of thermolabile may become challenging as elevated temperature is required during melting; If the gum is highly viscous, accurate dosing is not possible; Lack of precise form, shape, weight of dosage form; Grinding and compression: difficult to formulate chewing gum as tablets due to high moisture content.
Freezing, Grinding and Tabletting method	High-Tech, expensive equipments are required; Careful monitoring of humidity during manufacturing process become a challenge.