INTRODUCTION:

Medicated chewing gums are solid, single dose preparations with a base consisting mainly of gum that is intended to be chewed and not to be swallowed. They contain one or more active substances which are released by chewing and are intended to be used for local treatment of mouth diseases or systemic delivery after absorption through the buccal mucosa. Medicated chewing gum consists of a masticatory gum core with a coating that can be a film of polymers, waxes, sweeteners, sugars, flavors, or colors. The pharmacologically active ingredient can be present in the core, in the coating, or in both. The degree of the oromucosal absorption depends on the condition of the mucosa, the contact time, and the physicochemical properties of the active ingredient. A small un-ionized lipophilic molecule dissolved in saliva that is enzymatically stable is likely to be absorbed most readily. Regarding local actions, it is possible to achieve beneficial effects with medicated chewing gum that might be superior to those with lozenges.

Local effect

Chewing gum is an obvious drug delivery system for local treatment of diseases in oral cavity and in the throat, as sustaining the release of active substances may deliberately prolong exposure. Chewing gum is an ideal drug delivery system for this treatment area, the active substances are released as the gum is chewed, thus providing the potential for a high level of active substance to obtain local effect in the oral cavity. It is possible to design a chewing gum that releases active substances over a prolonged period.

Systemic effect

Systemic effects of active substances released from chewing gum can be achieved in two ways: in the “traditional” way, by swallowing the active substance, or buccally via absorption through the oral mucosa. The latter is of special interest. As buccal absorption avoids first-pass hepatic metabolism of the active substance, it could provide better bioavailability. The buccal absorption of nicotine has been studied extensively and is, therefore, a good example of buccal absorption obtained when using chewing gum as a drug delivery system².

Table 1: Merits and Demerits of Medicated Chewing Gum².

Merits

Demerits

 It is a convenient dosage form, which can be administered anytime, anywhere without need of water.

 Advantageous for patients with difficulty in swallowing tablets.

 Excellent for acute medication and pleasant taste.

 Avoids first pass metabolism and thus increases the bioavailability of drugs.

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

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

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

 Prolong chewing of gum may result in pain in facial muscles and ear ache in children.

 Additives in gum like a flavouring agent cinnamon can cause ulcers in the oral cavity and liquorice can cause hypertension.

 Risk of over dosage with medicated chewing gum compared with chewable tablets or lozenges, which can be consumed in a considerable number and within much shorter period of time.

Table 2: Components required for medicated chewing gum formulation^2,3,4.

Component	Function	Example
Water insoluble gum base
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, polyvinyl alcohol 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)
Plastisizers	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
Water soluble portions
Softners and emulsifiers	These are added to the chewing gum in order to optimize the chewability and mouth feel of the gum	Glycerin, 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 hydroxytoluene, butylated hydroxyani-sole, propyl gallate
Flavoring agents	To enhance consumer acceptabili-ty	Essential oils (citrus oil, fruit essences, peppermint oil, spearmint oil, mint oil, clove oil and oil of win-tergreen) and synthetic or artificial flavors
Bulking agents	Used if low calorie gum is desired	Polydextrose, oligofructose, inulin, fructooligosac-charides, guargum hydrolysate, indigestible dextrin
Compression adjuvant	To ease the compression process	Silicon dioxide, magnesium stearate, calcium stea-rate, talc

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)

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 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 flavour. In a carefully controlled room, the gum is cooled for up to 48 h. 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 thermolabile 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 (Thermolabile)

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 chewing gum (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 -15⁰C 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 -78.5⁰C, 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 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 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, 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

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.

In order to make the production of medicated chewing gum easier, Cafosa has developed Health in Gum, an innovative concept for the pharmaceutical industry. Health in Gum is an excipient, a directly compressible powder gum containing a mix of ingredients.

Health in Gum is specially designed for in-house use in pharmaceutical facilities and does not require specific chewing gum production equipment. It performs excellently using standard tabletting equipment.

Health in Gum offers an innovative drug delivery system that benefits from all the advantages of chewing gum and also contributes to improved compliance. It has been created to simplify the manufacturing process of chewing gum in a quick and cost-effective way. It is directly compressible and works at room temperature, which allows the use of thermosensitive APIs².

Factors Affecting on Release of Active Ingredient^2,3,5

A) Contact time

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

B) Physicochemical properties of active ingredient

Physicochemical properties of active ingredient play 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.

C) 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 suggests 60 cycles per minute chewing rate for proper release of active ingredient.

D) 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.

In-vitro drug release testing apparatus⁶

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 et al. They have studied the effect of chewing surfaces, twisting movements of surfaces and temperature of test medium on release rate of drug from medicated chewing gum.

Another novel dissolution apparatus has been developed for MCG by Rider JN et al. The apparatus consists 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. In 2000, European Pharmacopoeia published a monograph describing a suitable apparatus for studying the in-vitro release of drug substances from MCG. The chewing machine consists of a temperature-controlled chewing chamber in which the gum piece is chewed by two electronically-controlled horizontal pistons driven by compressed air. The two pistons transmit twisting and pressing forces to the gum, while a third vertical piston, (“tongue”) operates alternately to the two horizontal pistons to ensure that the gum stays in the appropriate position. 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 chew rate of 60 strokes per minute.

Marketed chewing gum products

There are several marketed chewing gum products, few of which are as given below.

Marketed products of medicated chewing gum

Products

Drug

Indication

Nicorette®

Nicotinell®

NiQuitin CQ®

Fluorette®

Vitaflo CHX®

Advanced+®

HEXIT®

Stay Alert®

Travvell®

Nicotine

Fluoride

Chlorhexidin

Chlorhexidine

Caffeine

Dimenhydrinate

Smoking cessation

Prevention of dental caries

Antibacterial

Prevention of caries

Antibacterial

Obesity

Motion sickness

Conclusion:

Since chewing gum in recent years has gradually been accepted as a possible drug delivery system, there seems to be novel areas for drug administration in various diseases or conditions where pharmacological intervention is indicated and where medicated chewing gum may prove advantageous. Today, there is a tendency to treat life-style illness by means of medicated chewing gum. Non-medicated chewing gum might improve aspects of memory. A continuous research and development of gum bases is going on. Further research into chewing gum with low or no calorie count will be necessary if gum users request these types of gums. Medicated chewing gums have several advantages including patient convenience, which in turn promotes higher degree of treatment compliance. Chewing gum might be considered more discreet than taking tablets, and it can be administered without water. It is advantageous for patients who have difficulties in swallowing tablets and it can be used for acute medication. If the gum has a pleasant taste, it will give a feeling of fresh mouth and can even inhibit bad breath. Moreover, medicated chewing gum may be a choice for children as chewing gum is highly accepted in this age group. Medicated chewing gum should of course be considered as a drug delivery system and the same precautions should be taken as for other delivery systems. Children (>5 years old) may prefer chewing gum as a route of drug administration than oral liquids or tablets. The use of medicated chewing gum is feasible as a local treatment of diseases or various conditions of the oral cavity. From a pharmaceutical and clinical point of view medicated chewing gum may also be an interesting drug delivery system compared with the traditional ways of administration. There is a special interest in obtaining systemic effect by means of medicated chewing gum that until now has only has been established in nicotine therapy for smoking cessation. In the future, new medicated chewing gums are expected and may serve as a way of drug administration.

REFERENCES:

1. European Pharmacopoeia. Council of Europe Strasbourg, 6^th ed. 2008: pp. 719.

2. Bumrela S, Kane RN, Dhat P. Medicated Chewing Gum: New Reformulation Technique. www.pharmainfo.net. 2008.

3. Potnis VV, Runwal AV, Lone KD. Chewing Gums Are Mobile Drug Delivery Systems. www.pharmainfo.net. 2008.

4. Ezhumalai K, Ilavarasan P, Rajalakshmi AN, Sathiyaraj U, Murali Mugundhan R. Medicated Chewing Gum-A Novel Drug Delivery Technique For Systemic and Targeted Drug Delivery. Int J Pharm & Techn. 2011; 3 (1): 725-744.

5. Jacobsen J, Christrup LL, Jensen NH, Medicated Chewing Gum: Pros and Cons.

6. Kvist C, Andersson SB, Fors S, Wennergren B, Berglund J, Apparatus for studying in vitro drug release from medicated chewing gums. Int J Pharm. 1999; 189: 57–65.

7. William P, Millind T. A Comprehensive Review On: Medicated Chewing Gum. Int J of Research in Pharmaceutical and Biomedical Sci. ISSN: 2229-3701.

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10. Sutradhar KB, Khatun S. Medicated chewing gum: An Unconventional Drug Delivery System. Int Current Pharm Jou. 2012, 1(4): 86-91.

11. Morjaria Y, Irwin WJ, Barnett P, Chan RS, Conway BR. In-Vitro Release of Nicotine from Chewing Gum Formulations. Dissolution Tech. 2004: 12-15.

12. Chewing gum, medicated, European, Pharmacopoeia 5th Ed., Supplemented 5.2 Council of Europe, Strasbourg, 2005; 3136–3137.

13. Sameja K, Raval V, Asodiya H, Patadiya D, Chewing Gum: A Modern Approach To Oral Mucosal Drug Delivery, IJPRD, 2011, 4(03): May-2012 (001 - 016).

14. Am J Drug Deliv. Jacobsen J, Christrup LL, Jensen NH: Medicated Chewing Gum: Pros and Cons. 2004, 2(2):75-88.

Received on 12.01.2015 Accepted on 04.03.2015

Asian J. Pharm. Tech. 2015; Vol. 5: Issue 1, Pg 50-55

DOI: 10.5958/2231-5713.2015.00009.4