There are several advantages to using chewing gum to administer drugs. It is non-invasive, readily accepted, and can be given at almost any time and everywhere. Stability of the therapeutic agent is easily maintained during storage because of packaging that keeps it away from oxygen, light, and water. Gum chewing can have local effects in the mouth and also systemic effects after the active agents have been swallowed, or absorbed through the oral mucosa. Drug absorbed directly via the buccal membrane avoids metabolism in the GI tract and the first-pass effect of the liver; it might therefore be to administer a reduce dose in chewing gum Compared to other oral delivery system⁴. Superior technology and comprehensive knowledge of chewing gum, together with the addition of medicated chewing gum in the European pharmacopoeia in 1998, have contributed to the high acceptance of this recent system of drug delivery. These days, MCG meets the same superior quality of standards as tablets as per current good manufacturing practice (cGMP) guidelines and it can be easily formulated to obtain different release rates of active pharmaceuticals which enabling distinct patient group targeting. Particularly in children, MCG may be a more favored method of drug administration compared with oral liquids or tablets⁵.

Advantages of MCG^6-8

1. Does not require water to swallow, hence can be taken anywhere

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

3. Highly acceptable by children

4. Excellent for acute medication

5. The treatment can, if required, be terminated at any time

6. Drugs that are released from chewing gum and swallowed, will be introduced in the gastrointestinal tract either dissolved or suspended in saliva and thus the drug will be presented in a readily bioavailable form

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

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

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

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

11. Pleasant taste

Disadvantages^{9, 10}

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. Additives in gum like flavoring agent, Cinnamon can cause Ulcers in oral cavity and Liquorice cause Hypertension.

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

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

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

Composition of MCGs:

Chewing gum is a mixture of natural or synthetic gums and resins, sweetened with sugar, corn syrup, artificial sweeteners and may also contain coloring agents and flavor. The basic raw material for all chewing gum 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

A. Water insoluble chewable gum base portion

B. Water-soluble bulk portion

A. Water insoluble chewable gum base portion

Water insoluble gum base generally comprises Elastomers, Resins, Fats and Oils, and Inorganic fillers.

1. Elastomers:

They provide elasticity, gummy texture and cohesion to the chewing gum. These are again divided into Natural and Synthetic elastomers.

Natural elastomer Natural rubbers like Latex or Natural gums such as Jelutong, Lechi Caspi, Perillo, and Chicle.

Synthetic elastomers like polyisobutylene and butyl rubber are used¹¹.

2. Plastisizer:

These are used to regulate cohesiveness of product. These are again divided into Natural and Synthetic Plastisizer.

Natural Plastisizers include Natural rosin esters like Glycerol Esters or Partially hydrogenated Rosin, Glycerol Esters of Polymerized Esters, Glycerol Esters of Partially dimerized Rosin and Pentaerythritol Esters of Rosin.

Synthetic Plastisizers include Terpene Resins derived from α-pinene and or d-limonene¹².

3. Fillers or Texturizers:

Provide texture, improve chewability, and provide reasonable size of the gumlump with low dose drug. Commonly used fillers are Magnesium and Calcium Carbonate, Ground Limestone, Magnesium and Aluminium Silicate, Clay, Alumina, Talc, Titanium Oxide and Mono/ di/ tri Calcium Phosphate^{12, 13}.

B. Water-soluble bulk portion

A water soluble portion contains Softners, Emulsifiers, Colourants, Sweetners, Sugarless Components, Bulking agents and Flavouring agents.

1. Softners and Emulsifiers:

These are added to the chewing gum in order to optimize the chewability and mouth feel of the gum. Softners include Glycerin, Lecithin, Tallow, Hydrogenated Tallow, Mono/ di/ tri-Glycerides, Fatty acids like Stearic acid, Palmitic acid, Oleic acid and Linoleic acid¹¹.

2. Colourants and Whiteners:

It may include FD and C type dyes and lakes, fruit and vegetable extracts, Titanium Dioxide¹³.

3. Sweetners:

These are of two types, Aqueous and Bulk.

Aqueous Sweetners can be used as softners to blend the ingredients and retain moisture. These include Sorbitol, hydrogenated Starch hydrolysates and Corn Syrups. Corn syrup keeps gum fresh and flexible.

Bulk Sweetners include Sugar and Sugarless components. Sugar Components include Saccharides like Sucrose, Dextrose, Maltose, Dextrin, Fructose, Galactose, and Corn Syrup¹⁴.

4. Sugarless Components:

These include sugar alcohols such as Sorbitol, Manitol, Xylitol, hydrogenated Starch hydrolysate. High intensity artificial Sweetners can also be included to provide longer lasting sweetness and flavour perception e.g. Sucralose, Aspartame, salt of Acesulfame, Alitame, Saccharin, Glycerrhizin, Dihydrochalcones^{12, 14}.

5. Bulking agents:

These are used if low calorie gum is desired. Examples of low caloric bulking agents include Polydextrose, Oligofructose, Inulin, Fructooligosaccharides, Guargum hydrolysate, Indigestible Dextrin¹².

6. Flavouring Agents:

A variety of flavouring agents are used to improve flavour in chewing gum includes essential oils, such as Citrus oil, fruit essences, Peppermint oil, Spearmint oil, Mint oil, Clove oil and Oil of Wintergreen. Artificial flavouring agents can also be used^{12, 14}.

Manufacturing Processes:

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

1. Conventional/ Traditional method (Fusion)¹⁴

Components of gum base are softened or melted and placed in a kettle mixer to which sweeteners, syrups, active ingredients and other excipients are added at a definite time. The gum is then sent through a series of rollers that forms 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 flavor. In a carefully controlled room, the gum is cooled for up to 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.

Limitation¹⁵:

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

2. Such a chewing gum composition is difficult to form into chewing gum tablets because often their moisture content (2-8%).

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

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

2. Cooling, Grinding and Tabletting Method (Thermo liable)^{8, 16}

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 temperature of the refrigerated mixture is around ̶ 15°C or lower. Amongst the various coolants like liquid nitrogen, hydrocarbon slush use of solid carbon dioxide is preferred as it can give temperatures as low as ̶ 78.5°C, 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.

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.

Use of grinding agents:

To prevent the gum from sticking to the grinding apparatus, 2-8% by weight of grinding aid such as alkaline metal phosphate, an alkaline earth metal phosphate or maltodextrin can be incorporated.

Tabletting:

Once the coolant has been removed from the powder, the powder can be mixed with other ingredients such as binders, lubricants, coating agents and 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. It requires equipment other than conventional tabletting equipment and requires careful monitoring of humidity during the tabletting process which is the major limitation.

3. Use of direct compression chewing gum excipients^{8, 12}

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 a mixture of polyol(s) 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).

Factors Affecting Release^17-19:

The release rate of an active substance is determined not only by the formulation of the chewing gum but also by the properties of the active substance and of the individual chewing the gum. The chewing gum – The water content of gum base is very low and the gum binds lipophilic substances very firmly. In order to obtain the optional formulation it is possible to

1. Decrease the release rate of highly hydrophilic substances

2. Increase the release rate of lipophilic substances

3. Achieve a more complete release of lipophilic substances

4. 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.

5. Physicochemical properties of active ingredient: Physicochemical properties of active ingredient plays very important role in release 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.

6. 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.

7. Changing the water solubility of the active substance will increase or delay the release. A similar effect may be obtained by changing the hydrophilic/lipophilic balance of the chewing gum formulation. The simplest way of achieving this is to increase or decrease the amount of gum base. An increase in the gum base will make the formulation more lipophilic and thus reduce the release rate of a given active substance. In principle, it is possible to manufacture products with a very low gum base content, but in practice a portion of chewing gum containing less than 20% gum base will have inferior chewing properties and may not be considered a viable formulation. Instead of changing the gum base content, it is far more effective to change the release properties by adding solubilizers to the formulation. This method enables release from the chewing gum of even highly insoluble substances, e.g. Miconazole. However using solubilizers requires specially designed gum bases as the solubilizer affect the texture of chewing gum. This may result in residual product becoming soft to an unacceptable degree after a very short period of chewing. Other methods are available for instance nicotine can be formulated as complex bound to a cation exchange resin leading to a prolonged release. This ion exchange principle could of course, also be used for other ionic substances. It is also possible to granulate the active substance with hydrophilic components, melted lipids, or to mix the active substance with a melted polymer.

8. The active substance: The release rate of an active substance depends on the solubility of the active substance in water and saliva. Highly hydrophilic substance will be almost completely released within 10 to 15 minutes. Substances with solubility in water or less than 0.1 ̶ l g/100ml are lipophilic components of the gum base and thereby show a slow and incomplete release. Active substances may be found in the form of salts or compounds with different solubilities, e.g. pro-drugs, thus the compound offering the best properties for achieving optimal release may be selected. Chlorhexidine can serve as an example apart from pure chlorexidine, chlorhexidine is available as different salts with different solubility. A special compound or pro-drug may be obtained by formulating a complex with an active lipophilic substance, e.g. by using cyclodextrines. This will result in a compound with higher water solubility and consequently increased release. It is also possible to increase or delay the release of an active substance by changing the physical form through a variety of coating and encapsulating techniques of the substance particles. A hydrophilic or a hydrophobic coating may encapsulate the active substance. To reduce the release rate a coating with ethyl cellulose can be used.

9. The individual: For medical chewing gum as for other pharmaceutical products is an inter-patient variance. Additional to conventional pharmaceutical formulations, other interpatient variations apply for a chewing gum formulation. When the individual is chewing the gum it may be regarded as an extraction process. Consequently, the release is related to the time the gum is being chewed to the frequency and intensity by which the individual is chewing, and it depends on the amount and composition of the individual’s saliva.

Characteristic of ideal drug candidates for chewing gum²⁰:

1. The drug should not be have any type of disagreeable taste and it should not be irritant to oral mucosa this can affect patient compliance.

2. The drug should be water soluble and should have suitable pKa for mucosal absorption.

3. The particle size of the drug should be kept below approximately 100μm to avoid unpleasant gritty feeling during chewing.

Characteristic of ideal medicated chewing gums²⁰:

1. They should not require water for administration and should not disintegrate with in the mouth.

2. They should have a pleasing mouth feel.

3. They should be compatible with taste masking

4. They should exhibit low sensitivity to environmental condition such as humidity and temperature.

5. They should allow high drug loading.

6. They should be manufactured and processed easily.

Evaluation¹⁷:

1. Test for Uniformity of Content:

Unless otherwise prescribed or justified and authorized medicated chewing gum with content of 2 mg or less than 2 percent of the total mass of gum comply with test.

2. Uniformity of mass:

Uncoated medicated chewing gum and unless otherwise justified and authorized coated medicated chewing gum comply with the test for uniformity of mass of single- dose preparations.

3. Weight variation:

Weight of the ten chewing gums is taken in a one batch then average weight is calculated from that standard deviation is calculated. As per individual monograph (According to USP).

4. Hardness:

Hardness in simple term is the property of material by which it is able to hold all its constituents in an intact form. Hardness is amount of strength of chewing gum to withstand mechanical shocks of handling in manufacture, packaging and shipping and tablet should be able to withstand reasonable abuse when in the hand of consumer. Hardness of chewing gum will be evaluated by Monsanto hardness tester. Hardness is measured in kg/cm².

5. Stickiness:

The MCG placed on the plain surface, mass of 250 gm Teflon hammer collide on it for period of ten minute. The frequency of hammering was about 30 / minute. After 10 minutes, sticking of mass to the hammered surface was observed and reported.

6. Drug release from medicated chewing gum:

It has been reported commercially that the drug release from medicated chewing gum as per the specification given in European Pharmacopoeia and is determined by applying a mechanical kneading procedure to a piece of gum placed in a small chewing chamber containing a known volume of buffer solution.

7. Stability studies of synthetic gum base:

10 gm of synthetic gum base was stored in bottle at 50º C for 30 days. After 30 days the gum was examined for natural ageing and physical nature.

Applications:

1. Dental caries^8,
21

Prevention and cure of oral disease are obvious targets for chewing gum formulations. It can control the release rate of active substances providing a prolonged local effect. It also reelevates plaque pH which lowers intensity and frequency of dental caries. Fluoride containing gums have been useful in preventing dental caries in children and in adults with xerostomia. Chlorhexidine chewing gum can be used to treat gingivitis, periodontitis, oral and pharyngeal infections. It can also be used for inhibition of plaque growth. 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. The bitter taste of chlorhexidine can be masked quite well in a chewing gum formulation.

2. Systemic therapy^8,
22

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, and 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. Nicotine is 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 nicoretteÒ 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: 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: 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.

Stability of chewing gum²³:

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

Marketed MCG Products^{24, 25, 26}:

Table 1: Some of the popular marketed MCG products

Marketed MCG	Active Ingredients	Indication
Stay alert®	Caffeine	CNS stimulant
Endekay®	Vitamin C (ascorbic acid)	Vitamin supplement
Orbit white® Happydent white® Trident white® Recaldent®	Calcium as a tricalcium phosphate	Dental hygiene and tooth Whitening.
Fluogum® Fluorette®	Fluoride as a sodium fluoride	Prevention of dental caries
Aspergum®	Aspirin	Pain relief
Hexit® Advanced	Chlorhexidine	Antibacterial
Niquitin cq® Nicorette®	Nicotine	Smoking cessation
Travel gum®	Dimenhydrinate	Motion sickness
Zolf stress gum®	Extract of Ashwagandha, passion flower and jujube fruit and calcium carbonate	Reduce the symptoms associated with stress, anxiety and depression
Chew away gum® Slim n trim®	Extract of Hoodia gordonni-nature's calcium channel blockers	Appetite supressant for weight loss
Zolf virility gum®	Extract of Haw thorn Berry, Horny Goat Weed, Damiana Leaf, Muira Puama Leaf, Ginkgo Biloba Leaf, Catuaba Bark Extract, Saw Palmetto Berry	Increase male sexual desire and Performance

CONCLUSION:

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. Generally, it takes time for a new drug delivery system to establish itself in the market and gain acceptance by patients, however chewing gum is believed to manifest its position as a convenient and advantageous drug delivery system as it meets the high quality standards of pharmaceutical industry and can be formulated to obtain different release profiles of active substances. For most drugs there are realistic possibilities of formulating them into a suitable chewing gum delivery system, although active agents with an extremely bitter taste may not be suitable candidates. Poorly water-soluble drugs require specialized formulation techniques to promote release, and these techniques are reasonably well developed. In the future, we may see drugs formulated into chewing gum in preference to other delivery systems to deliver drugs locally to the oral cavity. The reason is simple that the chewing gum delivery system is convenient, easy to administer anywhere, anytime and its pleasant taste improves patient compliance. Thus, it can be concluded that the chewing gum can be used, as a carrier for vast categories of drugs where extended release and the local action is desired. Chewing gum can be used without water, at any time. Now a day, MCG is gaining more attention as a very good vehicle to administer active principles in pharmaceuticals and nutraceuticals. Since the development cost of a new chemical or a drug molecule is very high, the pharmaceutical companies are focusing on development of new drug delivery system for existing drug with an improved efficacy and bioavailability together with reduced dosing frequency to minimize side effects. Hence the rational for using chewing gum as a possible drug delivery system is justified.

REFERENCES:

1. Chien YW. Novel Drug Delivery Systems. Marcel Dekker, New York. 1992.

2. Jacobsen J, Christrup LL and Jensen N-H. Medicated Chewing Gum. Am J Drug Deliv. 2 (2); 2004: 75-88.

3. Conway B. Chewing Gum as a Drug Delivery System. The Drug Delivery Companies Report. 2; 2003: 33-35.

4. Surana A. Chewing Gum: A Friendly Oral Mucosal Drug Delivery System. International Journal of Pharmaceutical Science Review and Research. 4; 2010: 68-71.

5. Malke S, Shidhye S, Desai AS and Kadam VJ. Medicated Chewing gum-A novel option. Indian drugs. 43 (3); 2006: 191-198.

6. Ezhumlai K, Rajalakshmi AN, Ilavarasan P, Sathiyaraj U and Mugundhan RM. Medicated Chewing Gum- A Novel Drug Delivery Technique For Systemic and Targeted Drug Delivery. International Journal of Pharmacy and Technology. 3; 2011: 725-744.

7. Mateti UV, Adla N, Rajakannan T and Valakkathala R. Insulin Chewing Gum: Need of the day for Diabetic patients. International Journal of Pharmaceutical Investigation. 1; 2011: 131-134.

8. Naik H and Gupta S. Medicated Chewing Gum- Updated Review. International Journal of Pharma Research and Development. 2; 2010: 66-76.

9. Gupta V, Wakhloo R, Mehta A and Gupta SD. Prophylactic Antiemetic Therapy with Ondansetron, Granisetron and Metoclopramide in Patients Undergoing Laparoscopic Cholecystectomy under GA. Journal of Medical Education and Research. 2; 2008: 74-77.

10. Tucha L and Simpson W. The Role of Time on Task Performance in modifying the effects of Gum Chewing on Attention. Journal of Appetite. 56; 2011: 299-301.

11. Patel VP. Medicated Chewing Gum: A Review. International Journal of Universal Pharmacy and Life Sciences. 1; 2011: 111-128.

12. Basani G, Venkata RD, Rao YM. Medicated Chewing Gum – A Novel Approach to improve Patient Compliance. International Journal of Research in Pharmaceutical and Biomedical Sciences. 2 (1); 2011: 23-32.

13. Zyck DJ, Greenberg MJ, Barkalow DG, Marske SW, Schnell PG and Mazzone P. Method of making coated chewing gum products containing various antacids. US Patent 6,645,535, 2003.

14. Athanikar NK and Gubler SA. Process for manufacturing a pharmaceutical chewing gum. US Patent 6,322,828.

15. Cherukuri SR and Bikkina K. Tabletted chewing gum composition and method of preparation. US Patent 4,753,805, 1988.

16. Mochizuki K and Yokomichi F. Process for the preparation of chewing gum. US Patent 4,000,321.

17. European Pharmacopoeia. Strasbourg: European Directorate for the Quality of Medicines. Chewing Gums: Medicated. 2004; 5th ed: pp. 260 and 601.

18. Lee WW. Chewing gum as a delivery vehicle for pharmaceutical and nutraceutical substances. Pharm Tech On-line. 2; 2001: 1-11.

19. Barabolak R, Hoerman K, Kroll N. Chewing gum profiles in the US population. Community Dent Oral Epidemiol. 19; 1991: 125-6.

20. Kulkarni AS, Dias RJ, Alookar NH and Mali KK. Medicated chewing gums. The Indian Pharmacist. 2005: 17-20.

21. Dodds MWJ, Hsieh SC and Johnson DA. The effect on increased mastication by daily gum chewing on salivary gland output and dental plaque acidogenicity. J Dent Res. 70; 1991: 1474-1478.

22. Nemeth-Coslett R, Benowitz NL, Robinson N and Hennigfield GE. Nicotine gum: chew rate subjective effects and plasma nicotine. Pharmacol Biomed Behav. 29, 1988: 747-751.

23. Sallstan G, Thoren J, Barrefand L and Sohue G. Skarping long term use of nicotine chewing gum and mercury exposure from dental amalgum filling. J Dent Res. 75; 1996: 594-598.

24. Happydent chewing gum. Available from: URL: www.prefettivanmelle.in/happydent.

25. Trident chewing gum. Available from: URL: www.tridentgum.com.

26. What is Recaldent? Available from: URL: www.recaldent com/c-what-is.asp.

Received on 20.10.2012

Modified on 25.10.2012

Accepted on 01.11.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(6): November–December, 2012, 293-299