INTRODUCTION:

MCG has become the most convenient drug delivery system in present age which appropriate for a wide range of active substances. Chewing gum has been very well received by the parents for use in children. Children particularly may consider chewing gum as a more preferred method of drug administration compared with oral liquids and tablets. Chewing gum is being used worldwide since ancient times after man experienced the pleasure of chewing 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. 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 contained. During the chewing process the drug contained in the gum product is released from the mass into saliva and could be absorbed through the oral mucosa or swallowed reaching stomach for gastro-intestinal absorption.

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. The first commercial chewing gum “State of Maine purespruce gum” was marketed in 1948 in the U.S.A. The first patent was filed in 1869. The gum was intended as dentifrices but it has never been marketed. The first Medicated chewing gum “Aspergum” was launched in 1928. This chewing gum is still available and contains acetylsalicylic acid. Another commercially available medicated chewing gum is dimenhydrinate – containing chewing gum for motion sickness. Consequently, today chewing gum is a convenient drug delivery system, which is appropriate for a wide range of active substances. Majority of therapeutic agents are absorbed in the oral mucosa. The drugs which show significant buccal absorption, dosage forms such as Chewing Gum permits more rapid therapeutic action compared to other oral dosage forms. Oromucosal drug delivery is a means to improve drug bioavailability. Administration of drugs directly into the oral cavity is an attractive route for both local therapy and systemic delivery of drugs which inherently exhibit variable bioavailability after oral dosing or low bioavailability due to high fast pass metabolism in the GIT, Liver or Skin, Further this route allows fast onset of drug action compared to the conventional oral route. Medicated chewing gum (MCG) is nothing but a gum base containing an active core or coating or both.

Figure 1: Medicated Chewing gum

Medicated Chewing Gum (MCG) is containing masticatory gum base with pharmacologically active ingredient and intended to use for local treatment of mouth diseases or systemic absorption through oral mucosa. MCG is considered as vehicle or a drug delivery system to administer active principles and nutrition that can improve health, and 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 administration. Many therapeutic agents are absorbed in the oral cavity.

Chewing gum dosage form for buccal delivery:^[^3,17]

Dosage forms such as mouthwashes, erodible/chewable buccal tablets, and chewing gums allow release of drugs for only a short period and thus there producibility of drugs absorption is comparatively poor. Application of bioadhesive semisolid gels creates considerable technical problems in the buccal absorption. Although medicated chewing gums pose difficulties in regulating the dose administered, they still have some advantages as drug delivery devices, particularly in the treatment of diseases in the oral cavity and in nicotine replacement therapy. Some commercially available chewing gums are Caffeine chewing gum, (Stay Alert®,) and Nicotine chewing gums (e.g. Nicorette ® and Nicotinell®). The permeability of nicotine across the Buccal mucosa is faster than across the skin. However, chewing gum slowly generates a steady plasma level of nicotine rather than a sharp peak as experienced when smoking. Possible swallowing of considerable amount of nicotine during chewing may lead to decreased effectiveness of the chewing gum due to first pass metabolism and gastrointestinal discomfort. It is a major challenge to optimize the dose-response relationship of nicotine administered in a chewing gum.

Advantages of MCG:^{[1, 5]}

1. Does not require water to swallow so can be easily taken anywhere.

2. Compatible 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. Bypasses first pass metabolism and thus increases the bioavailability of drugs.

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

8. Gum does not reach the stomach which leads to the minimal effect of formulation in the gastrointestinal tract.

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

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

11. Duration of action is increased.

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

13. Stimulates flow of saliva in the mouth.

14. Neutralizes plaque acids that form in the mouth after eating fermentable carbohydrates.

15. Helps whiten teeth by reducing and preventing stains.

Disadvantages of MCG^[^{4- 11]}

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 side effects like diarrhea.

3. Additives in gum like flavoring agent and the products obtained from natural sources like Cinnamon can cause Ulcers in oral cavity and liquorice cause Hypertension.

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

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

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

Ideal requirements for drug profile:^[^15]

1. The drug should not have any type of disagreeable taste, this can affect patient compliance.

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

Physico Chemical Properties of Drug:

· High salivary solubility

· PH independent solubility

· Tasteless

Patient Related Factors:

· Non toxic to oromucsa and salivary ducts

· Non carcinogenic

· Should not cause tooth decay

· Should not cause tooth decay and oromucosa staining Should not affect salivary flow rate

Anatomy and physiology of oral mucosa:^[^{12, 13]}

The oral mucosa can be subdivided into two general regions, the outer vestibule and oral cavity. Microscopically the oral mucosa consists of three main layers:

A. Oral epithelium

B. Lamina propria

C. Sub mucosa

A. Oral epithelium:

The epithelium of mouth consists of stratified, squamous epithelium, which may be either keratinized or non-keratinized. Keratinized epithelium is dehydrated, mechanically tough and chemically resistant. It is found in oral cavity such as mucosa of gingival and hard palate. Nonkeratinized epithelium is relatively flexible and is found in areas such as the soft Palate, the floor of mouth, the lips and the cheeks. The epithelium of the oral cavity is supported by the basement membrane. The membrane separates the epithelium from the underlying connective tissue layer. This process is represented in four morphological layers

• Basal layer

• Prickle cell layer

• Intermediate layer

• Superficial layer

B. Lamina propria:

The lamina propria contents a sheet of connective tissue containing collagen elastic fiber and cellular components in hydrated ground substance. It also consists of blood capillaries and nerve fibers which serves the mucosa. The blood vessels in the laminapropria are mainly engaged in the delivery of drug moieties in systemic circulation.

C. Submucosa:

· A submucosa may or may not be present deep to the dense layer of the lamina propria, depending on the region of the oral cavity. The submucosa usually contains loose connective tissue and also adipose connective tissue or salivary glands and also overlying bone or muscle within the oral cavity. Saliva is a hypotonic, watery secretion containing variable amount of mucus, enzyme, antibodies and inorganic ions .The surface of mucus membrane is constantly washed by a stream of about 0.5 to 2L of saliva daily produce in the salivary gland the chief secretion is supplied by three pairs of glands i.e. the parotid, the sub maxillary and the sublingual glands.:

Figure 2: Generalized Structure of Oral Mucosa

Composition of MCG:^[^5,
14]

Generally medicated chewing gums comprises of two parts: - A. Water insoluble chewable gum base portion. B. Water soluble bulk portion.

A. Water insoluble chewable gum base portion

The gum base comprises of a complex mixture of elastomers, resins, fats, emulsifiers, waxes, antioxidants, fillers and flavoring agents etc. In general, the gum bases will be present 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.

Elastomers:

It provides elasticity; gummy texture and cohesiveness to the chewing gum. It can be incorporated in amount of 15 to 45% of the total gum base. Two types of elastomers can be used in MCG formulation such as: -

Natural elastomers:

Natural rubbers like Latex or Natural gums such as Jelutong, LechiCaspi, Perillo and Chicle.

Synthetic elastomers:

Butadiene, styrene copolymers, Polyisobutylene, isobutylene isoprenecopolymers, polyethylene mixtures, and non-toxic vinyl polymer, such as polyvinyl alcohol.

Elastomer solvents:

These are used to soften the elastomers base component. Such elastomers 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 45.0% to 70.0%, by weight of the gum base.

Plasticizers:

These are used to regulate cohesiveness of product. Plasticizers used in MCGs are categorized into two types such as natural and synthetic.

i. Natural Plasticizers:

Natural resin esters like Glycerol esters or partially hydrogenated resin, Polymerized glycerol esters, Glycerol esters of partially dimerized resin and Pentaerythritol esters of resin.

ii. Synthetic Plasticizers:

Terpene resins derived from α-pinene and/or d-limonene.

Fillers or Texturizers:

The purpose of adding fillers to the formulation is to provide texture, improve chew ability and to provide reasonable size of the gum lump with low dose drug. It can be added in a range up to 50%. e.g. Magnesium and Calcium Carbonate, Ground Limestone, Magnesium and Aluminium Silicate, Clay, Alumina, Talc, Titanium Oxide and Mono/ Di/ Tri Calcium Phosphate.

Resins:

They are used as mastication substance and also act as a binding agent between elastomers and fillers. They maintain a balance between elasticity and plasticity properties of the formulation. Natural and synthetic resins are used in MCGs.

i. Natural resins:

Glycerol esters from pine resins.

ii. Synthetic resins:

Polyvinyl acetate. It acts as a de-tackifier i.e. prevents the gum from adhering to the teeth and also from being divided into pieces during chewing.

B. Water soluble portion:

The water soluble portion comprises of softeners, emulsifier, and sweeteners, flavoring agent, colors and antioxidants.

Softeners and Emulsions:

These are added to soften the mixture and to obtain the required chewing consistency and mouth feel of the formulation. Emulsifiers act by promoting the uptake of saliva into the chewing gum during chewing. Softeners include Glycerin, Lecithin, Tallow, Hydrogenated Tallow, Mono/ Di/ Tri Glycerides, Fatty acids like Stearic acid, Palmitic acid, Oleic acid and Linoleic acid.

Colorants and Whiteners:

Generally FD and C type dyes and lakes, fruit and vegetable extracts, Titanium Dioxide are used. The coloring agents containing pigments can be incorporated in amounts up to about 6% and Titanium dioxide may be incorporated in amounts up to about 2% by weight of the gum composition.

Sweeteners:

The amount of sweetener is selected as per the desired sweetness, and this amount will vary according to the type of the sweetener selected. Sweeteners are present in amounts up to 50% by weight of the gum composition. There are two types of sweeteners are used in MCGs such as Aqueous and Bulk sweeteners.

Aqueous sweeteners:

These are acting as softeners to mix the blend and retain the moisture. e.g. Sorbitol hydrogenated Starchhydrolysate and Corn Syrups.

Bulk sweeteners:

Bulk sweeteners are of two types such as Sugar components and Sugarless components.

Sugar components:

Saccharides like Sucrose, Dextrose, Maltose, Dextrin, Fructose, Galactose and Corn Syrup.

Sugarless components:

Sugar alcohols Such as Sorbitol, Mannitol, Xylitol, hydrogenated Starch hydrolysate.

High intensity artificial Sweeteners can also be included to provide longer lasting sweetness and flavor perception e.g. Sucralose, Aspartame, salt of Asesulfame, Alitame, Saccharin, Glycyrrhizin, and Dihydrochalcones.

Bulking agents:

Bulking agents are used to produce required bulk of chewing gum when potent drug or low-dose drug is to beincorporated.Theseare used if low calorie gum is desired. E.g. Polydextrose, Oligofructose, Inulin, Guargumhydrolysate, Indigestible Dextrin.

Flavouring Agents:

Flavouring agents are used to improve flavour in chewing gum. It can be used in amount of 0.01 to 1% e.g. Citrus oil, Fruit essences, Peppermint oil, Spearmint oil, Mint oil, Clove oil and Oil of Wintergreen. Artificial flavoring agents can also be used.

Active component:

In MCG the active component can be present in its core or coating or both. The proportion of active component may vary from 0.5 to 30% of the final gum weight. A small, unionized, lipophilic and enzymatically stable active agent is supposed 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 then slowly and completely absorbed Ideal requirements for drug Profile is that 1. The drug should not have any type of disagreeable taste, which may affect patient compliance. 2. The particle size of the drug should be kept below 100μm to avoid unpleasant gritty feeling during chewing.

Manufacturing processes:

There are three methods are available for the preparation of Medicated chewing gum such as: -

A. Conventional/Traditional method.

B. Freezing, grinding and tableting method C. Direct compression method.

A. Conventional/Traditional Method ^[16]

The components of gum base were softened or melted between 50 and 70°C and placed in a large kettle mixer and was grounded thoroughly. Then the above mixture is purified by using a straining apparatus and high speed centrifuges. Then to the above gum mass flavoring agent, softeners, sweeteners and API are mixed well by using equipment with strong rotating blades to produce amass with the desired consistency. Then the gum mass is sent through a series of rollers, to form into a thin, wide ribbon like structure during this process, a light coating of finely powdered sugar was added to prevent the gum from sticking and to enhance the flavor. Finally the gum is cooled for up to 48 hours which allows the gum to set properly and is cut to the desired size.

LIMITATIONS:

1. Thermo liable drugs are restricted for this method due to high temperature.

2. It is difficult to control the accuracy and uniformity of drug dose due to lack of uniformity in melting and mixing of highly viscous gum mass.

3. This type of chewing gum composition is difficult to form into chewing gum tablets because of their moisture content (2-8%).

4. There may be chances of sticking of gum base to the punches.

5. Lack of precise form, shape or weight of dosage form.

B. Freezing, Grinding and Tableting Method:^[^17]

This method was developed to avoid the problems associated with the conventional method .

Freezing and grinding:

The chewing gum base is cooled to a temperature around -15^oC or lower by using some coolants at which the composition is sufficiently brittle and would remain brittle during the subsequent grinding step without adhesion to the grinding apparatus. 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^oC. It sublimes readily on warming the mixture and is not absorbed by the chewing gum composition. It 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. 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 is mixed with chewing gum composition and solid carbon dioxide before grinding. This prevents agglomeration of the grounded chewing gum particles. e.g.:- Precipitated silicon dioxide

Use of grindingagents:

To prevent the gum from sticking to the grinding apparatus, 2-8% by weight of grinding aid is added. e.g.:- Alkaline metal phosphate, Alkaline earth metal phosphate, Maltodextrinetc But practical use of these substances is limited because of highly alkalinity. Hence may be incompatible with acidic ion sable therapeutic agents. They also tend to remain in the composition and final chewing gum tablet and thus may create problem for therapeutic and safety point of view. After the composition is ground to a powder, the coolant can be removed by allowing the coolant to evaporate.

Tableting:

After 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 blade mixer or a high shear mixer. Otherwise a Fluidized Bed Processor (FBP) can be used for this purpose. The granules so obtained can be mixed with antiadherent like talc. Then the mixture is blended in a V type blender and was screened. Now the mixture is ready for compression. Compression can be carried out by any conventional process like punching.

Limitation:

It requires equipment other than conventional tableting equipment and careful monitoring of humidity.

C. Direct Compression Method ^[18,
19]

Free flowing directly compressible excipients are available in the market to prepare MCG tablets. Pharmagum developed by SPI Pharma and Health in gum developed by CAFOSA, have become available in the market. Chemically, it is a mixture of polyols (sorbitol/Xylitol/Mannitol) and of sugar with gum, plasticizers and anticaking agents. Pharmagum is available in three forms namely Pharmagum S, M and C. Pharmagum M has 50% greater gum base compared to Pharmagum S. Pharmagum S consists primarily of gum base and sorbitol. Pharmagum M contains gum base, Mannitol and Isomalt.

Advantages:

MCG made by this gum material can be directly compressed by using a conventional tablet press with rapid and low cost development of MCG. Thermo sensitive APIs can also be processed as it does not require high temperature. This method is also useful for water sensitive APIs. The limitations of melting and freezing can be overcome by the use of these excipients.

Evaluation parameters of medicated chewing gum^[^20]

1. Hardness

The hardness and texture of the Medicated Chewing Gum is determined by texture analyzer.

2. Thickness

The thickness of the Medicated Chewing Gum is determined by screw gauge and expressed in millimeter.

3. Friability

The friability of the Chewing Gum is measured by Roche friabilator. It is expressed in percentage (%). Ten Chewing Gum is weighed (Winitial) and transferred to the apparatus. The friabilator was operated at 25 rpm for 4 mins. The Chewing Gum is weighed again (Wfinal). The %friability was then calculated by:

F= (Winitial-Wfinal/Winitial) X 100

4. Weight Variation

Twenty Chewing gums are weighed and the average weight is calculated. Then the Chewing gum is weighed individually. The percentage weight deviation of each Chewing gum from average weight is calculated using the following formula..

% Deviation= (Avg weight-Individual weight/Avg weight) X 100

As per specifications given in European Pharmacopoeia:

5. 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.

6. 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.

7. Drug release from medicated chewing gum:

It has been reported commercially that the drug release from medicated chewing 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. 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.

Future trends:^[^{16, 23]}

Chewing gum not only offers clinical benefits but also is an attractive, discrete and efficient drug delivery system. Previously, the only treatment for some disease was surgical procedure but now more and more disease can be treated with Novel Drug Delivery Systems. It takes time for a new drug delivery system to establish itself in the market and gain acceptance by patients and 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.

The potential of MCG for buccal delivery, rapid onset of action and the chances for product line extension makes it an attractive delivery system. Reformulation of an existing product is required for patent protection, additional patient benefits and conservation of revenues.

CONCLUSION:

A chewing gum formulation must have a pleasant taste and texture. The active substances not have an unpleasant, bitter, or metallic taste because the active substance will be released in the oral cavity and remain there for a longer period of time (usual chewing time is 10 to 20 minutes). 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, huge interest in this mode of drug delivery system for a wide variety of other indications exists and continuously grows. Clinical trials studies have confirmed the advantages to be gained by exploiting the effects of chewing gum and the convenience of the delivery and the possibilities of buccal absorption and local effect in mucosa. After one trial study it was found that chewing gum is possibly a safer drug delivery system for active substances that are susceptible to abuse. Chewing gum as a drug delivery system is to be expanded into additional therapeutic areas and the most important thing is that the delivery form is acceptable to all users. Clinical trials and market research have proven this to be the case. In the future, new formulations will enter the market and chewing gum will become a much more common drug delivery system.

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Received on 27.11.2015 Accepted on 28.12.2015

Asian J. Pharm. Tech. 2016; Vol. 6: Issue 1, Jan. - Mar., Pg 24-30

DOI: 10.5958/2231-5713.2016.00004.0