INTRODUCTION:

The choice of the correct medication distribution system is essential to the development of a pharmaceutical product. A different drug delivery system provides added benefits for patients that provide new exciting opportunities and therefore increase profitability. Due to the various advantages provided by the "oral route" it is the most recommended approach between patients and physicians. The most popular route is primarily due to its ease of administration¹.Available chewable dosage forms include soft pills, tablets, gums and latest one chewy squares. The chewing gum used as a DDS has enormous prospects in both prevention of smoking and oral health areas. “As per the European Pharmacopoeia and the 1991 recommendations for pharmaceutical dosage types, the Committee for Medicinal Products for Human Use (CPMP) describes medicated chewing gums” as “solid single dose preparations with a base consisting mainly of gum that is intended to be chewed but not to be swallowed, providing a slow steady release of the medicine contained”.

Medicated chewing gums are preferred to be chewed for particular time period, must deliver the dose, later the remaining mass are discarded. During the chewing cycle the substance in the gum product is released from the mass into saliva and absorbed through the oral mucosa or swallowed to the stomach for gastrointestinal absorption².

MCG is known as a drug delivery tool or device for implementing active concepts which can improve health and nutrition. It is the new device for clinical applications in "nutraceuticals, counter-medicines and pharmaceuticals"³. Chewing gum is a beneficial distribution system of medications with low water or salivary solubility meant to act in the oral cavity. Acetyl Salicylic Acid containing MCG was commercialized in 1928⁴. Chewing gum offers unique growth opportunities over conventional medicines. Numerous ingredients are now used in the medicinal chewing gum. Types include fluoride for dental caries prophylaxis, chlorhexidine as a local disinfectant, smoking cessation nicotine aspirin as an analgesic, and caffeine as a remain alert treatment. The United States business accounts approx. 50 per cent of the medicated chewing gums world market. The medicated gum contains an active ingredient in, or on, the surface. The first patent for chewing gum production was documented in 1869, and granted to Mr. W. F. Semple in Ohio. Patent No. 98,304. Aspergum ®, in 1928⁵the first medicinal chewing gum, was developed. This chewing gum includes acetyl salicylic acid; the analgesic agent. Dimenhydrinate-containing chewing gum is another commercially available prescription chewing gum for motion sickness.

Advantages of MCG^6-8

· Beneficial for patients who have difficulty in swallowing

· No or less application of water to swallow

· Beneficially for specific medications

· Act against dry mouth, oral thrush and dental caries

· Quite suitable for children

· Increases bioavailability of drug by preventing first pass metabolism

· Rapid action.

· No direct contact of higher concentrations of active component in the stomach, thereby decreasing cause of insensitivity of gastric mucosa

· Stimulates saliva flow in mouth

· Whiten teeth to minimize and also avoid stains

Disadvantages of MCG^9-13

· MCG relating to chewable lozenges and tablets there is possibility of overdose when taken in substantial amounts and at shorter duration.

· MCG formulation with sorbitol can induce diarrhoea and flatulence.

· Prolonged chewing on the gum can cause facial muscle aches.

· Chlorhexidine oromucosal use is limited mainly due to its staining properties on teeth and tongue and bad taste.

· In gum additives such as cinnamon, flavouring agent can cause ulcers in oral cavity and also hypertension is induced by liquorice.

Saliva and Chewing GUM¹⁴

Saliva which is considered as most important a defensive system in the body is activated by chewing gum. Saliva is important for maintain good oral condition/ health. Saliva supports three primary defensive features (anticaries):

1) Food debris are diluted and removed

2) Plaque acids are neutralized and dissolved by the bicarbonate present

3) Remineralization lesions of primary dental caries by calcium and phosphate ions

Saliva is considered as the strong oral antioxidant and to increase saliva production without medication can be done easily by chewing gum. Due to gustatory action of chewing and flavour stimulation saliva production can be increased¹⁵.

Composition of MCG:

Resins and Natural or synthetic gums, corn syrup, artificial sweeteners, sweetened with sugar, along with colouring agents and flavourings are the composition of chewing gum. Chicle which is obtained from sapodilla vine is the important raw material for all chewing gum. Since chicle is difficult to obtain and also due to its higher cost, consequently, other synthetic materials such as some polymers and polyvinyl acetate or natural gum are used as gum base¹⁶. These components are depicted in Figure 1.

Generally, the chewing gum consists of two components,

1. Gum base that is water soluble generally consists of inorganic fillers, fats, elastomers, oils and resins.

2. Portions with water soluble components Includes softeners, bulk Sweeteners, colours, high Intensity Sweeteners, antioxidants and Flavouring agents.

Figure 1: Components of Chewing Gum

Elastomers:

Elastomer offers elasticity and influences the strength of the gummy. Natural elastomer which is known as natural rubber, such as plant gum or latex such as chicle, Puerile Jelutong.

Plasticizer:

Added to control the quality of the drug. It is classified as synthetic and natural goods. Plasticizers of natural origin include-esters of natural resins such as Resin esters Pentaerythritol, Glycerol esters, Polymerized glycerol esters, partially hydrogenated resin esters and partially dimerized resin esters Glycerol.

Plasticizers of synthetic origin include -Resins from or d-limonene and/α-pinene derived from terpene.

Texturizer and Fillers:

Include more texture, improve chewability and give the gum lump a reasonable size with a low dose drug. Talc, Magnesium carbonate, magnesium silicate, Calcium Carbonate, Aluminium Silicate, titanium oxide, Clay, Titanium Oxide, alumina and Mono/Di/tri Calcium Phosphate are commonly used fillers.

emulsifiers and Softeners:

To improve the palatability and chewability of the gum these are added to the chewing gum. Tallow, mono/di/tri-glycerides, Glycerin, Hydrogenated Tallow, lecithin, fatty acids i.e. linoleic acid, palmitic acid, stearic acid and oleic acid are used as softeners.

Colourants and Whiteners:

It could include titanium dioxide, extracts of vegetables and fruits, and dyes and lakes (types FD and C).

Sweeteners:

There are two types of sweeteners namely, Aqueous and Bulk. In order to combine the ingredients and to preserve moisture as softeners aqueous sweeteners can be used. These consists of hydrogenated hydrolysates for maize, corn syrups and sorbitol. In order to keep gum fresh and flexible Corn syrup can be used. The components of bulk sweeteners are sugar and sugarless. Saccharides are sugar components, such as dextrin, sucrose, galactose, maltose, and fructose. Components that are sugar-less contains mainly alcohols i.e., hydrogenated starch hydrolysate, sorbitol, xylitol and mannitol. To provide longer perception of flavours and sweetness, artificial sweeteners with high intensity can also be used e.g. Glycyrrhizin, Acesulfame salt, Aspartame Saccharin, Alitame Dihydrochalcones and Sucralose.

Bulking Agents:

It's often added to less- calorie gums. Sources of less-calorie bulking agents involve guar gum hydrolysate, Polydextrose, dextrin indigestible, inulin and Oligofructose.

Flavouring Agents:

The use of a numerous flavouring chemicals in chewing gum consists of mainly essential oils for examples, winter green clove oil, citrus oil, spearmint oil, fruit essence, oil, peppermint oil. We can also use chemical flavouring agents.

Active component:

In the core or coat, or both of MCG, the active pharmaceutical ingredient can be present. The proportion can be between 0.5 and 30 percent of the final weight of the gum. The active agent that unionised, enzymatically stable, lipophilic, small are more easily and quickly absorbed. Duration of 10-15 mins of chewing, a saliva- dissolvable component is extracted completely, when lipid-soluble material dissolves in the base of the gum and is only gradually and fully ingested. MCG comprises of coated congealed gum in the core. Insoluble aqueous base which can be added along with flavours and sweeteners are presented in the core of the gum. The surface may be spread as a film of waxes, polymers, sweeteners, colours and flavours or as alcohol paste or dense sugar.

Formulation Development Process:

Diagrammatic presentation of the formulation of MCG is shown in Figure 2. Following are the thrree main methods of chewing gum preparation:

a) Traditional/conventional method (Melting).

b) Latest advancements in process and technology

c) Direct Compression Method^17.

Figure 2: Formulation development process

a) Traditional/ conventional method (melting):

Components of the gum base are softened or melted and positioned in a mixer to this at particular time interval syrups, sweeteners, other excipients and active ingredients are added. Then gum is sent into a long, broad rope, through a set of rollers that shape. To keep the gum free from attaching and to improve taste, thin layer of sugar adulterant or evenly powdered sugar is applied during the process. The gum is refrigerated in a carefully controlled environment for 2 days. It helps to set the gum correctly. Eventually, the gum is sliced to the required shape and size desired size and refrigerated. Humidity and temperature are regulated carefully¹⁸.

Drawbacks:

Limitations involved in this method include¹⁹:

1. Due to the elevated melting temperature this method cannot be used for heat sensitive drugs.

2. The control of drug dose uniformity and accuracy is complicated mainly due to mixing and melting highly viscous gum components

3. Absence in accordance to accurate dosage form, shape or weight

4. Not so readily adaptable technologies to accommodate the intense production requirements required to produce pharmaceutical products.

5. Due to its moisture content (2-8 percent), it is difficult to form chewing gum tablets by gum composition. If such a composition is tried to grind, the machine would lock, attach to blades, displays attachment to Punches, and it can be difficulty to compact.

B) Latest advancements in process and technology²⁰

Shortcomings of traditional method which include defect in similar texture, weight and structure and imprecision in uniformity of weight can be solved by advanced electronic instruments. The different processing phases involved in the production of MCG using the new technology include

1. Melting: Softening of the surface of the gum in a base Melted at temperature more than 40°C to less than 60°C.

2. Mixing: To the melted gum base, sweeteners and syrups are added, and mixed slowly using slow mixing blades in a mixer in a mixer. Subsequently, an active ingredients, colours, fillers and softeners are applied and properly blended by a sigma blade mixer.

3. Extruding: Twin rope extruder transfers warm mass to extrude whole mass into twin rope.

4. Cooling: Twin rope is transmitted onto slow motion cooling belts, bathed in cool air currents (-15°C to -78.5°C).

5. Shaping: Cool mass is compacted into a gum carpet. The automated cutting and wrapping unit rolls into the correct shape. Marked in single pieces.

6. Conditioning: The chewing gum is transferred into a cooling space that closely monitors temperature and humidity. It provides the finished product strong endurance.

C) Direct compression method²¹

The production can be accelerated by using gum excipients that can be directly compressed. By using these excipients, the disadvantages of freezing and melting can be solved. For example, PHARMAGUM ® is the gum system that has been formulated by SPI Pharma. Pharma gum made of sugars and polyol (s) along with a chewing gum base. It is accessible as the powder that is directly compressed and free flowing that can be easily compressed to gum tablet by using standard tablet press causing reduced cost and quick production of the delivery system. Pharma gum is available as S, M and C forms. The gum base present in Pharmagum M is 50% greater than Pharmagum S. The components of Pharmagum S are sorbitol and gumbase. Whereas M form consists of mannitol, gumbase and isomalt. Use of these forms allows formulators to quickly and cost-effectively use a gum delivery system as compared to traditional methods.

Aspects related to formulation²²

· Exchange resins to which solid component Faster release can be obtained in presence of larger quantities of emulsifiers and softeners in the gum base whereas prolong release can be seen in hard gum^23.

· By incorporating techniques like solubilisation and cyclodextrin complexation in formulation relating to poorly soluble drugs, their aqueous solubility can be increased^24.

· Cation of lipophilic active components are bound favours-controlled delivery of drugs.

· Release of active ingredients can be modified and controlled by microencapsulation or agglomeration ^25-26.

Methodology Related to Drug Release Testing:

Apparatus used for drug release testing for MCGs is depicted in Figure 3. To determine the rate of drug release from gum formulation the fundamental concept involved is general chewing motion that causes the chewing of piece of gum that is positioned on the small chewing chamber that consists of required quantity of buffer solution at a particular given temperature²⁷. The chewing angle and intensity, which produce the shear force needed to show new gum surfaces determines the rate of drug release from the formulation. The inactive gum is converted to active dosage form and can be identified by temperature, water permeation and wetting ability and also by mechanical forces. According to sink condition, the rate of drug release is inversely proportional to the mass of gum base and directly proportional to the aqueous solubility of the drug component and chewing frequency²⁸.

Apparatus I. Compendial - Ph. Eur, chewing gum apparatus:

Ph. Eur. In 2000 introduced chewing apparatus for MCG ²⁹. The apparatus comprises of a chewing chamber, a third vertical piston and two horizontal pistons. To make sure that the gum remains in the correct position along the chew the vertical piston operates with two pistons placed horizontally in alternative manner. Many studies performed using this apparatus states the method is rough but reproducible³⁰.

Apparatus II. Noncompendial - Alternative chewing gum apparatus:

wennergren designed the commercially available non-compendial apparatus³¹. The chewing process involves the reciprocation of the lower surface alongside the twisting movements of the high surface which trigger chewing gum chewing at the same time as the test media is properly agitated. The lower central part is parallel to upper jaw flat surface. To produce operation in such a manner that the lower surface function as a small bowl with flat bottom the small brim in the lower surface is angled upward (45 degree). The bowl during mastication prevents the sliding of the gum.

Figure 3: Apparatus for in vitro drug release of medicated chewing gum

Evaluation Of MCG:

Structural analysis of MCG:

Visual inspection is carried out on various MCG formulation. Structural features of the gumbase was determined on understanding their moisture absorption, relative humidity, solubility studies and colour³². The formulations are physically evaluated for parameters such as weight variation, appearance, stickiness, hardness and plasticity.

Hardness/plasticity can be determined using Monsanto Type hardness tester.

Stickiness can be determined by placing the MCG on plane surface and allowing 250gms of cylindrical hammer to collide over it for duration of 10 mins. The frequency of hammering 30 per minutes. Sticking of product to the hammered surface is determined.

Chew out study:

Starting phase of chew out study consists of various parameters such as softness, sweetness, lubricating feel, cooling effect, texture, hardness, smoothness etc³³.

In vitro drug release:

The drug release through In vitro are based on following factors:

· Twisting angle of upper mastication jaw altered from (5˚ – 30˚).

· The distance between lower and upper masticating jaw altered from (1-2 mm)

· Lower masticating jaw chewing frequency altered from (20 strokes/minute to 120 strokes/ minute).

· Temperature altered from (30˚C – 40˚C)

In the lower chewing surface between the piston the chewing gum is placed. Due to the up and down stroke of lower masticating surface together with upper masticating surface twisting movement the chewing gum is masticated together with constant stirring of test medium. After required time interval small amount of artificial saliva is collected and analysed for drug content using analytical instrument such as UV spectrophotometer^34-35.

Stability study:

Stability study is carried out by keeping 10 gms of gum base in a bottle at 30˚C/65% RH corresponding to WHO guidelines for duration of six months. Any signs of physical deformities and aging in the gum can be checked after six months⁵⁰.

Safety description:

Various commercially available chewing gums mainly attach to various angles in the crowns, fillers and dentures. Pain in jaw muscle can occur due to over chewing. Compared to flavoured chewable tablets, chewing gum cause a small risk of overdosing or misuse. These MCG must be kept away from children in similar way as other medicines. It is adviced to check for any allergic responses as the MCG formulation contains various sweetening and flavouring agents⁵¹.

Applications:

MCG in Therapeutics:

By inducing production of saliva to prevent dental problems, chewing has caused greater application and recognition for MCGs. Plaque pH can be increased by using non-medicated gums and it also promotes production of saliva and reduces dental deterioration³⁶. Plaque and inflammation of gums can be diagnosed by using MCGs comprising Chlorhexidine. MGCs are important in treatments related to oral infections³⁷. For systemic implementable products MCG are used as one of the essential drug delivery agents. Through the buccal mucosa, the drug can be absorbed which are supplied from the gum in the oral cavity. The sublingual and buccal tablets that are used for systemic action can be substituted by MCG that acts as an alternative, as the main component is released more homogenously and it cover larger surface of oral cavity absorption. Systemic effects can be provided by MCGsin conditions such as smoking cessation^39, deficiency of vitamin C³⁸,fever and pain⁴⁰, motion sickness⁴¹, alertness⁴² and for local effect in conditions such as fresh breath⁴³, anti-carries^44, antibacterial⁴⁵, antiplaque⁴⁶ plaque acid neutralization⁴⁷, disinfection⁴⁸ and antifungal⁴⁹.

Dental Caries⁵²

Evident goals for chewing gum products include avoidance and treatment of oral illness. MCG is effective in managing the release rate of active substance which are used to provide increased duration of local effect. The potency and constancy of dental cavities can be decreased due to increase in plaque pH caused by MCG. In Adults and children suffering from xerostomia, fluoride containing gum cab be proved to be beneficial in reducing dental caries. Gingivitis, oral and pharyngeal infections and periodontitis can be prevented by administration of chlorhexidine containing MCG. Plaque development can also be inhibited.

Systemic Therapy:

Chewing gum as a medication delivery device may be beneficial for a variety of purposes, like;

· Cause of Pain-Therapy with mild headaches, anxiety and muscle aches can be managed with ease.

· Discontinuation of smoking- caffeine, silver acetate and lobeline in form of chewing gum products are used as smoking cessation agents which are clinically proven.

Natural occurring enzyme inhibitor known as Nicotine which are present in tobacco plant leaves are medicinal products which are used as an aid by smokers to quit the smoking mainly by decreasing the symptoms that occur during smoking cessation mainly due to withdrawal of nicotine. By which the patient can manage the dosage of medication according to his desire.

· Obesity- some of the active compounds such as caffeine, chromium, guaran, are indicated to be effective in reducing overweight. Craving can be reduced or controlled by Chromium which is mainly due increase in equilibrium of glucose and plasma. Caffeine and guarantee Some symptoms such as cold and cough, anxiety, acidity xerostomia, asthma, motion sickness etc, are some of the condition where MCG can be administered as this method can cause breakdown of fats and other lipids and provide relevant dynamic activity that is the thermal impact of food needed for the digestion, absorption and disposal of nutrients ingested or food and decreases the hunger sensation.

Future Scope:

· Chewing gum provides not only health advantages but is also an enticing, safe and effective drug administration device. Many years back, surgical procedure used as the main procedure to cure certain illness but in present situation varieties of diseases and disorders can be cured by using certain advanced drug delivery techniques.

· In the coming years chewable birth control pills would be available which can be another birth control choice for women. Ovcon 35 which is the birth control chewable drug approved by FDA will be launched by Warner Chilcott Inc^53-54.

Commercial MCGs:

Table 1 enlists various commercially available MCGs along with their manufacturing companies and uses.

Table 1: Commercial MCGs

Trade name	Active drugs	Company	Use
Nicorette	Nicotine	GSK	Smoking cessation
Nicotinell	Nicotine	Novartis	Smoking cessation
Fluorette	Fluoride	Fertin Pharma	Dental caries
Alert energy	Caffeine	Wringley Pharma	Stimulant
Travel	Dimenhydrinatum	Meda Pharma	Motion sickness
Chooz	Calcium carbonate	Insight Pharma	Antacid
Vitaflo CHX	Chlorhexidine		Preventing tooth decay

CONCLUSION:

According to the benefits of MCG, it is a novel drug delivery useful for both local and systemic delivery. Due to its buccal delivery of drugs, it offers protection against acid and enzymes, low first pass metabolism and good stability. Applications include treatments for motion sickness, pain, smoking, dental caries, tooth decay, GI problems, oral fungal infections, inflammatory problems etc. One more important application includes smoking cessation chewing. This is mainly due to chewing gum often gives the smoking habit a visible replacement and thus increases the possibility of effectively stopping it. For drugs used to treat diseases that require quick action, such as transit disease, headache and nausea, MCG can be proved as important or useful drug delivery system. To conclude, drugs can be formulated in the form MCGs to deliver medications directly into the oral cavity in comparison to other delivery systems as they are is simple, convenient and easy to administer with high patient compliance.

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