INTRODUCTION:

It is well known fact that the right drug delivery system is critical to the success of a pharmaceutical product. Pharmacological active agents or drugs are formulated into variety of dosage forms like tablets, capsules, injectables, inhalers, ointments etc considering physicochemical properties, pharmacokinetic and pharmacodynamic 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 ingredients¹.

A novel drug delivery system creates additional patient benefits that will add new competitive advantages for a drug and thus increase revenue. Oral route is the most preferred route amongst the patient and clinicians due to various advantages it offers.

One of the reasons that the oral route achieved such popularity may be in part attributed to its ease of administration². Medicated chewing gum (MCG) is the gum base incorporating drug(s)³ .

Chewing gum is being used worldwide since ancient times after man experienced the pleasure of chewing a variety of substance. One thousand years ago the Mayan Indians chewed tree resin from the sapodilla tree in order to clean their teeth and freshen their breath. Shortage of natural gum bases during World War II enhanced development of the synthetic gum bases that are used today. Chewing gum can be used as a convenient modified release drug delivery system. Medicated chewing gums are currently available for pain relief, smoking cessation, travel illness, and freshening of breath. In addition, a large number of chewing gum intended for prevention of caries, xerostomia alleviation and vitamin / mineral supplementation are currently available.

Chewing gum is a pleasure that almost everyone enjoys⁴. Chewing gums are mobile drug delivery systems⁵. Chewing gum usually consists of a gum core, which may or may not be coated. The water content of chewing gum is very low and requires no preservatives. Medicated chewing gums are defined by the European Pharmacopoeia and the guidelines for pharmaceutical dosage forms issued in 1991 by the Committee for Medicinal Products for Human Use (CPMP) as ‘solid single dose preparations with a base consisting mainly of gum that are intended to be chewed but not to be swallowed, providing a slow steady release of the medicine contained⁶. Generally, chewing gum is a combination of a water-insoluble phase, known as gum base and some other ingredients. These include powdered sugar whose amount and grain size determine the brittleness of the resulting gum, corn syrup and/or glucose which serve as humectants and coat the sugar particles to stabilize their suspension and keep the gum flexible, various softeners, food colorings, preservatives, flavorings etc.

Chewable tablets and Chewing Gum permits more rapid therapeutic action compared to per-oral dosage form.⁷ In Children particularly may consider chewing gum as a more preferred method of drug administration compared with oral liquids and tablets. It had shown that people chewing gum was better at keeping awake and alert, and that gum chewing eased tension. The anecdotal effect of chewing gum on weight loss has also been studied recently. Though there are many other interesting anecdotal effects that result from gum chewing, such as the easing of blocked ears.It can be used either for local (mucosal) treatment of mouth disease or for systemic (transmucosal) delivery by direct intraoral absorption through the buccal mucosa.⁸

HISTORY⁹

Chewing gum has an old and long history, in 50 AD, the Greeks sweetened their breath and cleansed their teeth by using mastiche, a resin from the bark of mastic tree. (The English word "masticate" is derived from the root word mastiche.) At the beginning of its history this product was not so much accepted by the public.The social acceptance of chewing gum, however, has increased dramatically over the years.As chewing gum has become more widely accepted and practiced, songwriters, film makers and authors have incorporated related themes into their works.

One thousand years ago, the ancient Mayan Indians of Yucatan chewed tree resin (chicle) from the Sapodilla tree. Spruce gum, which was manufactured in 1848, became the first chewing gum product to be manufactured commercially Called "STATE OF MAINEPURE SPRUCE GUM." However, its use was eventually replaced by paraffin, which is still being chewed in some areas.

During the 1860's, a New York photographer named Thomas Adams, realized the potential market for chewing gum products. He wrapped pieces of pure, flavorless chicle in colored tissue paper, packaged them in boxes, and left them on consignment with numerous drugstore owners. The gum was named Adams New York No.l. Public response to the product was very favorable.

The first patent for chewing gum, U.S. number 98,304 was filed on December 28, 1869 by Dr. William F. Sample, a dentist from Mount Vernon, Ohio. This product, consisting of liquorice and rubber dissolved in alcohol and naphtha, was initially intended to be used as a dentifrice.

In 1891, William Wrigley Jr., arrived in Chicago with $32 in cash with a desire to market his special variety of soap. Eventually, he switched from soap to baking powder sales and offered chewing gum premiums to merchants who became his customers. By 1892, when the premiums had become more popular than the baking powder, Wrigley launched his first chewing gum products, LOTTA and VASSAR. A year later, he developed JUICY FRUIT, and shortly thereafter, WRIGLEY's SPEARMINT gum.

Sugarless gum made its debut in the early 1950s, generally used sorbital as a sugar substitute. The first brand to be marketed was Harvey's followed by Trident and Carefree. In 1975, the Wm. Wrigley Jr. Company introduced the arrival of a new chewing gum product, Freedent, designed especially for denture wearers, which did not stick to most dentures as ordinary gum did.

Merits of MCG^10-14

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

2) Advantageous for patients having difficulty in swallowing,

3) Excellent for acute medication,

4) Counteracts dry mouth, prevents candidiasis and caries,

5) Highly acceptable by children,

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,

12) Stimulates flow of saliva in the mouth,

13) Neutralizes plaque acids that form in the mouth after eating fermentable carbohydrates,

14) Helps whiten teeth by reducing and preventing stains.

Demerits of MCG^15-19

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 Liquorice 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. Prolonged chewing of gum may result in pain in facial muscles and ear ache in children.

MANUFACTURING ^20,21

1. Gum Base:

Gum base is an inert and insoluble nonnutritive product used as a support for the edible and soluble of the chewing gum (sugar, glucose, poly oils and flavors) Other raw materials are generally grouped in the following classes:

2. Elastomers:

Including natural and synthetic rubbers. The gum base composition may contain conventional elastomer solvents to aid in softening the elastomer base component. Such elastomer solvents may comprise terpinene resins such as polymers of alpha-pinene or beta-pinene, methyl, glycerol or pentaerythritol esters of resins or modified resins and gums, such as hydrogenated, dimerized or polymerized resins or mixtures. The elastomer solvents may be employed in amounts from 5.0% to 75.0%, by weight of the gum base, and preferably from 45.0% to 70.0%, by weight of the gum base.

Synthetic elastomers such as butadiene, styrene copolymers, polyisobutylene, isobutylene isoprene copolymers, polyethylene mixtures, and non-toxic vinyl polymer, such as polyvinyl alcohol are widely used bases. The molecular weight of the vinyl polymer may range from 3,000 to 94,000. The amount of gum base employed varies greatly depending upon various factors such as the type of base used, the consistency of the gum desired and the other components used in the composition to make the final chewing gum product. In general, the gum base will bepresent in amount from 5% to 94%, by weight of the final chewing gum composition. Preferably, the gum base is used in amounts from 15% to 45% and more preferably in amounts from 15% to 35%by weight of the final chewing gum composition.

3. Plasticizers:

Waxes, vegetable oils, glycerides. Plasticizers or softeners such as lanolin, palmitic acid, oleic acid, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glyceryl lecithin, glyceryl monostearate, propylene glycol monostearate, acetylated monoglyceride, glycerine, natural and synthetic waxes, hydrogenated vegetable oils, polyurethane waxes, paraffin waxes, microcrystalline waxes, fatty waxes, sorbital monostearate, propylene glycol, may be incorporated into the gum base to obtain a variety of desirable textures and consistency properties.

4. Adjuvants:

Calcium carbonate, talc, or other charging agents are used. Mineral adjuvant such as calcium carbonate, magnesium carbonate, aluminum hydroxide, aluminum silicate, talc, tricalcium phosphate, dicalcium phosphate serve as fillers and textural agents.

5. Antioxidants:

An anti- oxidant such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate and mixtures there of, may be included as antioxidants.

6. Compression adjutants:

Suitable compression adjuvant such as silicon dioxide, magnesium stearate, calcium stearate and talc can be used in medicated chewing gum for ease of compression. The alkaline earth metal phosphates and alkali metal phosphates prevent caking and balling of “High” i.e. 2 to 8% moisture- containing chewing gum compositions during grinding.

Additionally, it has been discovered that maltodextrin enhances the grinding of “high” moisture-containing chewing gum compositions by absorbing moisture to allow lubrication in the gum as it separates into granules. If oil lubricants are used, it is preferred to be 0.4% to 1% by weight of the tableted chewing gum composition. The amount of glidant present in the tableted chewing gum composition is from 0.5% to 5% by weight of the tableted chewing gum composition. Those glidants useful are selected from the group consisting of alkali metal salts, talc, starch, polyhydric alcohols and mixtures.

Antiadherents function to prevent tablet granulations from sticking to the faces of the punches and the die walls, but most importantly, prevent adherence of chewing gum granules from adhering to one another, a phenomenon known as blocking. Anti- adherents may be added to the chewing gum composition while the composition is in the hoppers, or subsequent to grinding and are selected from the group consisting of silicates, silicon dioxide, talc and mixtures thereof present in amount of 0.2% to 1% by weight of the tableted chewing gum composition and preferably about 0.3 to about 0.6% by weight. Generally anti-adherent is a finely divided low bulk density powder, which is preferably water insoluble. The preferred anti-adherents are fumed silica and talc. The term-fumed silica is meant to include pyrogenic silicas, micron sized silicas and hydrated silicas.

7. Sweeteners

a) Water-soluble sweetening agents:

Xylose, ribulose, glucose, mannose, galactose, fructose, sucrose, maltose, invert sugar partially hydrolyzed starch, dihyrochalcones, monellin, steviosides, glycyrrhizin, and sugar alcohols such as sorbitol, mannitol, hydrogenated starch hydrolsates.

b) Water-soluble artificial sweeteners:

Soluble saccharin salts, i.e. sodium or calcium saccharin salts, cyclamate salts.

c) Dipeptide based sweeteners: L-

Aspartic acid derived sweeteners such as Aspartame, Alitame, methyl esters of L-aspartyl-L phyenylglycerine and Laspartyl- L 2,5-dihyrophenylglycine, L-aspartyl 2,5- dihydro-L phenylalanine – L aspartyl – L (1-cyclohexen) alanine.

d) Water-soluble sweeteners:

Derived from naturally occurring watersoluble sweeteners, chlorinated derivatives of ordinary sugar (sucrose, known as Sucralose)

e) Protein based sweeteners:

Such as thaumaoccous danielli (Thaumatin I and II) In general an effective amount of sweetener is utilized to provide the level of sweetness desired, and this amount will vary with the sweetener selected and are present in amounts from 0.0025% to 90% by weight of the gum composition.

8. Coloring Agents:

The coloring agents include pigments, which may be incorporated in amounts up to about 6% by weight of the gum composition, titanium dioxide may be incorporated in amounts up to about 2%. The colorants may also include natural food colors and dyes suitable for food drug and cosmetic applications.

9. Flavoring Agents:

Flavoring agents suitable for use are essential oils and synthetic flavors such as citrus oils, fruit essences, peppermint oil, spearmint oil, clove oil wintergreen oil, and anise oil.

Table 1: Optimal Properties of Drug.

Physicochemical

Properties of Drug

Patient Related Factors

High Salivary Solubility

pH independent solubility

Tasteless

Non-toxic to oromucosa and salivary ducts

Non-carcinogenic

Should not cause tooth decay

Should not cause oromucosa and teeth staining

Should not affect salivary flow rate

10. Active Component:

In medicated chewing gum active pharmacological agent may be present in core or coat or in both. The proportion of which may vary from 0.5-30% of final gum weight. A small, unionized, lipophilic and enzymatically stable active agent is likely to be absorbed more readily. A saliva soluble ingredient will be completely released within 10-15 minutes of chewing whereas lipid soluble ingredient will dissolve in the gum base and thereafter be slowly and completely absorbed. MCG consists of masticatory gum core that may be coated. The core is composed of an aqueous insoluble gum base which can be mixed with Sweetners and Flavours. The coating can be applied as a film of polymers, waxes, sweetners, flavours and colours or a thick layer of sugar or sugar alcohol. Shown in table 1.

MANUFACTURING PROCESSES ^22-24

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

1. Conventional/ Traditional method ( Fusion )

Components of gum base 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 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 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 thermoliable 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 (Thermoliable)

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 -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 the first step. Additional solid carbon dioxide and silica are added to the ground composition, and the composition is further ground in the second 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. The same process can be made multiple by adding incorporating additional carbon dioxide and/or precipitated silica at each step.

Certain additives can be added to the chewing gum composition to facilitate cooling, grinding and to achieve desired properties of chewing gum. These include use of anti-caking agent and grinding agent.

Use of anti-caking agent:

An anti-caking agent such as precipitated silicon dioxide can be mixed with chewing 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. However practical use of these substances is limited because these substances are highly alkaline and hence would be incompatible with acidic ionisable therapeutic agents. They also tend to remain in the composition and final chewing gum tablet and thus may be problematic for therapeutic and safety point of view.

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. 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

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 OF ACTIVE INGREDIENT²⁵

1) Physicochemical properties of active ingredient: It plays a 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.

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

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 of active 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.

SOME IMPORTANT FORMULATION ASPECT ^26-29

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 agglomeration are the methods to modify and control the release ofactive ingredient. Table no 2

Table No:2 Some of the commercially available chewing gum and trade mark.

SI. NO	Trade Mark (™)	Active substance	Aim
1	Aspergum	Aspirin	Pain Relief
2	Travell	Dimenhydrinate	Travel illness
3	Nicorette	Nicotine	Smoking cessation
4	Chooz	Calcium carbonate	Stomach acid , Neutralization
5	Stamil Vit C	Vit C	General health
6	Stay alert	Caffeine	Alertness
7	Brain	DHA and CCE	Enhanced brain activity

EVALUATION PARAMETERS:

Product performance test:

Two different types of tests are performed to assess the drug product characteristics: product quality and performance tests. Currently USP contains individual monographs with product quality tests for Nicotine Polacrilex and Nicotine Polacrilex Gum. Ph. Eur. has adopted a general monograph on medicated chewing gums and a monograph describing the apparatus for dissolution testing of medicated chewing gums.

In vitro drug release from MCG:

Unofficial single-module chewing apparatus:³⁰ One of the unofficial apparatus for carrying out dissolution studies of MCG was designed by Wennergren. This apparatus consists of a two-piston and temperature-controlled reservoir for dissolution medium, as shown in a schematic representation in Figure 1. The upper jaw has a flat surface that is parallel to the central part of the lower surface. The small brim of the lower surface is angled upwards (45 degrees) so that the lower surface functions as a small bowl with a flat bottom. This bowl prevents the chewing gum from sliding during mastication . Throughout one cycle of chewing, one piston on each side shift towards each other. When they get together, they press the MCG between them and then make a twisting association before returning to the preliminary point. To carry out a drug release test, a known quantity of chewing gum is placed in the 20 ml volume of dissolution medium, which is equilibrated to a temperature of 37oC. The pressing and twisting forces are transmitted to the gum through the pistons at a chewing rate of 60 strokes a minute. At specified time intervals, that is, 3, 5 and 10 min, samples are collected and analyzed to evaluate percentage drug release. Fig 1.

Fig. 1: schematic representation of unofficial single module chewing apparatus

Official MCG chewing apparatus:³¹ The official modified dissolution apparatus for assessing drug release from MCG, as per European Pharmacopoeia, is depicted in Figure 2 . In this apparatus, in addition to the pair of horizontal pistons (‘teeth’), the chewing chamber is supplied with a vertical piston (‘tongue’) working alternate to the horizontal pistons, which ensures that the gum is always positioned in the correct place during the mastication process.

If required, it is possible to construct the machine so that at the end of the chew the horizontal pistons rotate in opposite directions around their own axis to each other to attain maximum mastication. The temperature of the chamber can be maintained at 37±0.5oC 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 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 a minute. This most recent device seems promising, competent and uncomplicated to operate. Several studies have been carried out using the European Pharmacopoeia apparatus and the results indicate the methodology is rugged and reproducible.fig 2

In vivo ‘chew-out’ studies:³²

The in vivo release of active ingredient from chewing gum during mastication can be studied by recruiting a panel of sufficient numbers of tasters and scheduled chew-out studies. For the duration of the chewing process the drug contained within the MCG is released in the saliva and then it is either absorbed through oral mucosa or, if swallowed, it is absorbed through the gastrointestinal tract.

a. Release of drug in saliva:

Panel of volunteers is asked to chew the drug delivery device for a certain period of time and to assess the remaining quantity of active substance in the residual gum. In this way, the gums are really chewed and the formulation is subjected not only to the mechanical stresses of an artificial machine but also it undergoes all the phenomena involved in this process (increase of salivary secretion, saliva pH variation, swallowing and absorption by the oral mucosa, etc.) which can strongly influence the performance of the dosage form and the amount and rate of drug release. Optimized formulation with good consistency can be selected for the release of drug in saliva. Minimum Four human volunteers can be selected (two male and two female). Volunteers are instructed to rinse their mouth with distilled water and allowed to chewing the medicated chewing gum for 15 minutes, so that its maximum release has to be taken. Sample of saliva are taken after 2, 4, 6, 8, 10, 12, 14, 15 min. The saliva samples are made diluted in required solvent and absorbance is analyzed by suitable analytical method .

b. Dissolution test of residual medicated chewing gum: In this experiment, gums are tested by a panel of volunteers to verify the drug release process from the drug delivery system. Each person chews one sample of the tableted gum for different time periods (1, 5, 10, 15 min) 39. The residual gums are cut into small pieces, frozen and then ground till obtaining a fine powder. The residual drug content is determined by using suitable analytical method. The amount of drug released during mastication is calculated by subtracting the amount of residual active ingredient present in the gum from the total content, whereas pharmacokinetics can be determined from withdrawn blood samples at specific time intervals. The prerequisites of human volunteers, person-to-person variability in the chewing pattern, chewing frequencies, composition of individual salivary fluid and flow rate of saliva are a few limitations of chew-out studies.

c. Urinary excretion profile of medicated chewing gum: This method can be applicable only to those drugs which are excreted via urine. In that minimum four healthy human volunteer are selected for the study of formulations. Volunteers are strictly instructed that they should not take any medicine in the last 48 hour. They are fasted overnight, and emptied their bladder in the volumetric flask. Sample collection starts from blank of zero hour urine. Then sample collection is done on the 15 min, 1, 2, 3, 4, 6, 7, 8, 10, 11, 12, 24 hour intervals after administration of medicated chewing gum. The volunteers are asked to drink water at regular intervals of 30 min. and urine samples are analyzed by suitable analytical methods.

d. Buccal absorption test: Human volunteer swirled fixed volume of drug solution of known concentration at different pH value of 1.2, 5, 6, 6.5, 7, 7.5, 7.8, 8, in the oral cavity for 15 min and then expelled out. The expelled saliva is analyzed for drug content and back calculated for buccal absorption.

Factors affecting release of active ingredient from MCG:

1. Person-to-person variability: One of the reasons why MCG has not yet been fully exploited is because of the therapeutic uncertainty related to the drug delivery method that is, a patient’s mechanical chewing action. The gum’s therapeutic effect depends on chewing and as each person has his/her own chewing force, frequency and chewing time, which may lead to variation in results. The rate at which the subject chews gum also affects the amount of drug released. The average chewing rate is ~ 60 chews every minute. For this purpose, the release of nicotine from Nicorette chewed at different rates has been investigated. In that study it was found that a chewing rate of 1 chew every second gave a significantly (p < 0.05) higher release than a chewing rate of 1 chew every 8 s. An in vitro study prescribed by European Pharmacopoeia suggests 60 strokes a minute are sufficient for proper release of active ingredient.

2. Physicochemical properties of drug: The physicochemical properties of the active ingredient such as its molecular mass, ionized or non-ionized form, lipophilicity or hydrophilicity, stability to salivary enzymes (amylase) and its solubility in salivary fluid play very important roles in the release of drug from MCG and absorption of drug through oral mucosa. For example, the saliva-soluble ingredients will be immediately released within a few minutes, whereas lipid-soluble drugs are released first into the gum base and then slowly into salivary fluid. Aqueous solubility of API plays an important role in the release from chewing gum composition, that is, release of water-soluble drug (aqueous solubility > 1:10) is, in general, ~ 75% or more during 5 min of chewing and 90% or more during 15 min of chewing at a rate of 60 chews a minute. Drugs with aqueous solubility between 1:10 and 1:300 demonstrate up to 60% release during 10 min of chewing and between 50 and 90% release after 15 min of chewing.

3. Formulation factors: Composition and amount and type of gum base, solubilizing agents and softening agents may affect the rate of release of the active ingredient from MCG.

Possible absorption pathways ^33-36

The release of most water-soluble components from chewing gum is relatively rapid. Drug released from the chewing of medicated gum will be either absorbed from the buccal mucosa or, if swallowed, absorbed from the gastrointestinal tract. Drugs that are released from chewing gum and involuntarily swallowed will be introduced to the gastrointestinal tract in dissolved, diluted, or suspended form in saliva and so will be very easily bioavailable with a consequent fast onset of action as compared with solid oral dosage forms. To obtain the optimal formulation it is possible to decrease the release rate of highly hydrophilic substances and increase the release rate of lipophilic substances. Antihistamines (chlorpheniramine maleate, cetirizine HCl), appetite suppressants (phenylpropanolamine HCl or caffeine), expectorants (guifensin hydrochloride), antitussives (dextromethorphan, noscapine), opioids (codeine phosphate, codeine sulfate), nasal decongestants (phenylephrine HCl, pseudoephedrine, ephedrine HCl), analgesics and anti-pyretics (aspirin or acetaminophen), anti-inflammatories (ibuprofen, ketoprofen, naproxen), electrolyte and mineral supplements, antacids, laxatives, vitamins, ion exchange resins (cholestyramine), and anti-cholesterolamics such as most prescribed therapeutic categories can be potential possible targets for delivery in the form of MCG owing to its higher patient compliance and quick onset of action.

APPLICATIONS ^37-42

1. Dental caries

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

a) Pain-

Chewing gum can be used in treatment of minor pains, headache and muscular aches.

b) Smoking cessation-

Chewing gum formulation containing nicotine and lobeline have been clinically tested as aids to smoking cessation.

c) Obesity-

Active substances like chromium, guaran and caffeine are proved to be efficient intreating 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.

FUTURE OPPORTUNITIES:

Chewing gum not only offers clinical benefits but also is an attractive, discrete and efficient drug delivery system. Nowadays 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 and popularity by the 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. Finally, in the future, we may see that more and more 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 increases the product acceptability and patient compliance.

CONCLUSION:

A chewing gum formulation must have a pleasant taste and texture. Most active substances have an unpleasant, bitter, or metallic taste. Since the active substance will be released in the oral cavity and remain there for a longer period of time than is the case with ordinary delivery forms (usual chewing time is 10 to 20 minutes), unique expertise in taste definition, taste masking, and taste modification are essential to the success of a medical chewing gum product. Though chewing gum as a drug delivery system has currently gained wide acceptance only within smoking cessation and oral healthcare, vast interest in this mode of drug delivery for a wide variety of other indications exists and continues to grow. Clinical trials have confirmed the advantages to be gained by exploiting the effects of chewing gum, per se, the convenience of the delivery and the possibilities of buccal absorption and local effect. Furthermore, one trial has indicated that chewing gum is possibly a safer drug delivery system for active substances that are susceptible to abuse. As chewing gum as a drug delivery system is to be expanded into additional therapeutic areas, it is important that the delivery form is acceptable to the end-users. Clinical trials and market research have proven this to be the case. In the coming years, new formulations will enter the market and chewing gum will become a much more common drug delivery system.

REFERENCES:

1. Morjaria Y, Irwin WJ, Barnett PX, Chan RS, Conway BR. In Vitro Release of Nicotine From Chewing Gum Formulations, Dissolution Technologies, May 2004, 12-15.

2. Surana AS Chewing gum: A friendly oral mucosal drug delivery system. International Journal of Pharmaceutical Sciences Review and Research. 4(2);2010: 68-71.

3. Mary Bellis. The history of chewing gum and bubble gum. Available from: URL: http://inventors.about.com/od/ gstartinventions/a/gum.htm

4. Semwal R, Semwal D.K, Badoni R. Chewing Gum: A Novel Approach for Drug Delivery. The Journal of Applied Research. 10(3); 2010:124-131.

5. Naik H,Gupta S. Medicated Chewing Gums - Updated Review. International Journal of Pharmaceutical Research and Development. 2(11); 2010:66-76.

6. haudhary S.A, Shahiwala A.F. Medicated chewing gum – a potential drug delivery system. Expert Opin. Drug Deliv. 2010; 71-85.

7. Athanikar N.K., Gubler S. A. Process for manufacturing a pharmaceutical chewing gum. US Patent 6,322,828, 2001.

8. Gadhavi AG. et al. Medicated Chewing Gum - A 21st Century Drug Delivery System. International Journal of Pharmaceutical Science and Research. 2(8); 2011: 1961-1974, 1961-62

9. Cloys L, Christen A, Christen J. The development and history of chewing gum. Bulletin of the History of Dentistry. 1992, 40, 57-65.

10. Morjaria Y, Irwin WJ, Barnett PX, Chan RS, Conway BR: In Vitro Release of Nicotine from Chewing Gum Formulations. Dissolution Technologies. May 2004, 12-15.

11. Chien YW, Novel Drug Delivery Systems, Marcel Dekker, New York, II edition, Revised and expanded, 1992, 139-140.

12. Edgar W, Geddes D. Chewing gum and dental health - a Review, Br Dent J. 1990; 168: 173-177.

13. Jacobsen J, Christrup L.L, Jensen NH. Medicated Chewing Gum: Pros and Cons, American Journal of Drug Delivery.2 (2);2004: 75-88.

14. Conway B. Chewing Gum as a Drug Delivery System, The Drug Delivery Companies Report Autumn/Winter, 2003, 33-35.

15. Jacobsen J, Christrup LL, Jensen NH. Medicated Chewing Gum. American Journal of Drug Delivery. 2 (2);2004:75-88

16. Goldberg LD, Ditchek NT. Chewing gum diarrhea. Am J Dig Dis. 1978; 23(6):568

17. Addy M, Roberts WR. Comparison of the bisbiguanide antiseptics alexidine and chlorhexidine. II. Clinical and in vitro staining properties. J Clin Periodontol.:8(3):1981,220-30.

18. Munksgaard EC, Nolte J, Kristensen K. Adherence of chewing gum to dental restorative materials. American Journal Dentistry. 8(3); 1995:137-139.

19. Weil AT. Coca leaf as a therapeutic agent, American Journal Drug Alcohol Abuse. 5(1); 1978:75-86

20. Zyck DJ, Greenberg; MJ, Barkalow DG, Marske SW, Schnell PG., Mazzone P. Method of making coated chewing gum products containing various antacids. US Patent 2003; 6645535.

21. Jacobsen J, Christrup LL, Jensen NH. Medicated Chewing Gum: Pros and Cons, American Journal Drug Delivery. 2

22. Cherukuri Subraman R, Bikkina Kirshnayya Tabletted chewing gum composition and method of preparation, US Patent, 1988, 4, 753, 805.

23. Mochizuki Keizo, Yokomichi Fumio. Process for the preparation of chewing gum, US Patent, 1976, 4, 321.

24. http://www.spipharma.com/ProductsFolder/120ParmaGum/120Pharmagum.html

25. European Pharmacopoeia. Strasbourg: European Directorate for the Quality of Medicines. Chewing Gums: Medicated. 5th ed., 260 and 601, 200417, Barabolak R, Hoerman K, Kroll N. Chewing gum profiles in the US population, Community Dent Oral Epidemiol, 1991, 19, 125-126.

26. Jacobsen J, Bjerregaard S, Pedersen M. Cyclodextrin inclusion complexes of antimycotics intended to act in the oral cavity--drug supersaturation, toxicity on TR146 cells and release from a delivery system, Europian J Pharm Biopharm. 48(3);1999: 217-224.

27. Gudas V V, Reed M A, Schnell P G, Tyrpin H T, Russell M P, Witkewitz D L. Method of controlling release of caffeine in chewing gum. US Patent, 1998, 6,165,516.

28. Kvist C, Andersson SB, Fors S, Wennergren B, Berglund J. Apparatus for studying in vitro release from medicated chewing gum. International Journal of Pharmacy. 1999, 189, 57-65.

29. Rider JN, Brunson EL, Chambliss WG, Cleary RW, Hikal AH, Rider PH, Walker LA, Wyandt CM, Jones AB. Development and evaluation of a novel dissolution apparatus for medicated chewing gum products. Pharm Res. 1992, 9, 255-260.

30. Catharina Kvist, Sven Brje Andersson, Susan Fors, Bo Wennergren, and Johan Berglund. Apparatus for studying in vitro drug release from medicated chewing gums. International Journal of Pharmaceutics . 189;1999:57–65.

31. Shirzad Azarmi, Wilson Roac, Raimar Lobenberg. Current perspectives in dissolution testing of conventional and novel dosage forms. International Journal of Pharmaceutics. 328; 2007: 12-21.

32. Nagaich U, Chaudhary V. Formulation of medicated chewing gum of ondansetron hydrochloride and its pharmacokinetic evaluations. International journal of pharmaceutical Sciences and Research. 1(2); 2010:32-39.

33. Jabar A. Faraj, Rossella Dorati, Aurélie Schoubben, David Worthen. Development of a Peptide-containing chewing gum as a sustained release antiplaque antimicrobial delivery system. AAPS PharmSciTech 2007; 8(1).

34. Witzel F, Mackay. Chewing gum capable of releasing finely divided water-insoluble materials there from. US4238475; 1980.

35. Niazi S, Shemesh A. Chewing gum containing medicaments and taste maskers. US4639368; 1987.

36. Patel SS, Patel NM. Formulation - A doctor's note for gum. Pharmaceutical formulation and quality 2006.

37. Zoft Hoodia functional chewing gum for weight loss. Available from: www.zoft-hoodia-gum.com

38. Nazneen Z. Ratlam: Chewing gum as drug delivery system. Available from: http://www.pharmainfo.net./

39. Jain H, Shah M, Shah B. Medicated chewing gum: A Novel oral drug delivery. International Journal of Drug Formulation and Research. 1(3); 2010: 80-96.

40. Lee M. Cohen, Frank L. Collins Jr., Joseph W. Vander Veen, and Cameron C. Weaver The effect of chewing gum flavor on the negative affect associated with tobacco abstinence among dependent cigarette smokers. Addictive behaviors. 2010.1-6.

41. Manning RH, Edgar WM. In situ de- and remineralisation of enamel in response to sucrose chewing gum with fluoride or non-fluoride dentifrices. Journal of Dentistry . 26;1998:665-68.

42. Elisabeth J. Houtsmuller, Reginald V. Fant, Thomas E. Eissenberg, Jack E. Henningfield, and Maxine L. Stitzer. Flavor improvement does not increase abuse liability of nicotine chewing gum. Pharmacology, biochemistry and behavior, 2002; 72:559–568.

Received on 07.09.2012 Accepted on 28.10.2012

Asian J. Res. Pharm. Sci. 2(4): Oct.-Dec. 2012; Page 150-159