Medicated chewing gum

Formulation, Manufacture and Evaluation of Medicated Chewing Gum

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Medicated chewing gums (MCGs) are solid or semi-solid, single-dose preparations with a base consisting mainly of tasteless masticatory gums that are intended to be chewed but not swallowed. It is a drug delivery system that contains one or more active ingredients which are released by chewing. After dissolution or dispersion of the active ingredient(s) in saliva, drugs released from the gum within the oral cavity can act locally, be absorbed via the buccal mucosa, or from the gastrointestinal tract (when swallowed with the saliva).

The use of chewing gum as delivery systems have been promoted for certain peculiar needs. Sugar-free gums have been used to counteract dental caries by stimulation of saliva secretion. This has led to more widespread acceptance of medicated chewing gums. Medicated gums for delivery of dental products to the oral cavity are marketed in a number of countries, for example, fluoride-containing gums as an alternative to mouthwashes and tablets or chlorhexidine gum for treatment of gingivitis. The potential use of medicated chewing gums for treatment of oral infections has also been reported. MCG is also useful as a delivery system for agents intended for systemic delivery. This article reviews the fundamentals of medicated chewing gum, historical development, composition, production techniques, quality control tests as well as the advantages and disadvantages of medicated chewing gums as a drug delivery system.

Development and history of medicated chewing gum

Chewing gum is a pleasure that almost everybody enjoys. People have enjoyed chewing gum since ancient times after man experienced the pleasure of chewing a variety of substance. Chewing gum has an ancient history in 50 AD of Greeks sweetening their breath and cleaning their teeth using mastiche, a resin from the bark of mastic tree. Ancient Mayan Indians of Yucatan chewed chicle from the sapodilla tree.

John B. Curtis in 1848, made and marketed the first commercial chewing gum called “THE STATE OF MAINE PURE SPRUCE GUM”. Over time their company (Curtis Chewing Gum Factory) prospered, it was then that Curtis’ son found they need to improve the company and machines, so he developed a machine which mass-produced gums.

During the 1860’s Thomas Adams, a New York Photographer realized the potential market for chewing gum products. He wrapped pieces of pure, flavourless chicle in coloured 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 favourable.

On 28 December 1869, Doctor William F. Semple, a dentist from Mount Vernon, Ohio filed the first patent for chewing gum both as a confection and a pharmaceutical to protect teeth. This product comprises liquorice and rubber dissolved in alcohol and naphtha.

The first medicated chewing gum, Aspergum® containing acetylsalicylic acid was launched in 1924 in the United States of America but its use as a drug delivery system did not gain acceptance as a reliable drug delivery system until 1978 when nicotine chewing gum was released in the market.

The European Pharmacopoeia in 1991 defined the intended use of medicated chewing gum as the local treatment of mouth diseases or for systemic absorption through the oral mucosa or from the gastrointestinal tract.

Although modern chewing gums often consist of synthetic resins, Thomas Adams first manufactured MCGs with natural latex-base and issued the first patent of chewing machine to render chicle kneaded and smooth. Today, advancement in technology and extended know-how have made it possible to develop and manufacture medicated chewing gum with pre-defined properties.

Read Also: Formulation, Manufacture and Evaluation of Chewable tablets




Composition of medicated chewing gum

Medicated chewing gums are formulated with suitable excipients to enhance chewability, palatability and efficient delivery of the medicament. In addition to the active pharmaceutical ingredient(s), medicated chewing gums contain:

1. Gum base

This is the nonnutritive part of medicated chewing gum which does not dissolve while chewing. Usually, the gum base forms about 40% but can be up to 65%, and includes a complex mixture, insoluble in saliva, comprising mainly of elastomer, plasticizers, waxes, lipids and emulsifiers.

Medicated Chewing Gum: Typical formulation of gum base

Typical formulation of gum base

2. Elastomers

These are polymers with high elongation properties and elasticity. They provide elasticity and controls gummy texture. Examples include natural rubbers like latex or natural gums such as Jelutong, Lechi-caspi, Perillo, Chile gum, Niger gutta, Nispero etc. Artificial elastomers such as polyisobutylene, isobutylene, isoprene copolymer, styrenebutadiene copolymer, polyvinyl acetate etc, have also been used.

3. Plasticizers

Plasticizers are used to regulate the cohesiveness of the product. It promotes gum texture by applying plasticity and reducing brittleness. It also softens the elastomers. Plasticizers of both natural and synthetic origin have been used in the manufacture of chewing gum.  Examples include natural rosin esters like glycerol esters of partially dimerized rosin, glycerol esters of partially hydrogenated rosin, glycerol esters of polymerized esters, and pentaerythritol esters of rosin. Synthetic materials which are used as plasticizers include terpene resins derived from α-pinene and/or d-limonene.

4. Texture agents/ fillers

These include talc, calcium and magnesium carbonate, ground limestone, aluminium and magnesium silicate, alumina, clay, titanium oxide and mono/ di/ tri-calcium phosphate. They provide texture, improve chewing ability, and provide reasonable size of the gum lump with low dose drug. They also facilitate blending and other processing stages.

5. Lipid and Wax

The lipid and the waxes melt in the mouth to provide a cooling, lubricating feeling. The base may be wax free.

6. Softeners and Emulsifiers.

These are added to MCG in order to optimize the chewability and mouth feel of the gum. Softeners used in the manufacture of medicated chewing gum include tallow, hydrogenated tallow, glycerine, lecithin, mono/ di/ triglycerides, fatty acids like oleic acid, stearic acid, linoleic acid and palmitic acid.

7. Antioxidants

Antioxidants such as ascorbic acid, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and mixtures thereof, may be added to inhibit oxidation.

8. Flavouring agents

These are used to improve flavour in medicated chewing gums. Examples include essential oils, such as citrus oil, fruit essences, spearmint oil, mint oil, peppermint oil, clove oil, anise oil and oil of Wintergreen. Synthetic flavours can also be used.



9. Sweeteners

Sweeteners provide the desired sweetness of the product. Water-soluble sweetening agents e.g., sorbitol, hydrogenated starch, corn syrups, help to retain moisture and freshness of the finished product. They also act as a plasticizer or softening and binding agents.

High-intensity synthetic sweeteners can also be added to provide longer lasting sweetness and flavour perception. They produce lower calorie due to the partial absorbance in the intestine. Examples include sucralose, aspartame, alitame, saccharin, glycyrrhizin, dihydrochalcones etc.

10. Colouring agents.

Colourants are added to improve the colour of the formulation. Example include FD & C type dyes and lakes, fruit and vegetable extracts, titanium dioxide.

11. Anti-tack agents

These are included in MCG to prevent self-adhesiveness also known as blocking in materials which have a tendency to stick together (e.g., rubbers). It also reduces fragmentation of the gum and prevents it from attaching to the teeth during mastication. Examples include α-cellulose and vegetable proteins.

12. Anti-caking agents

Anti-caking agents (e.g., precipitated silicon dioxide, solid carbon dioxide) are used to prevent caking and lump formation. These materials improve flow properties and rehydration and help for good packaging. They also help extend shelf life and detract dispersibility.

A typical chewing gum formulation is shown in the table below.

Medicated chewing gum: Example of chewing gum formulation

Example of chewing gum formulation

Equipment used in the manufacture of medicated chewing gum

These include:

  1. Weighing balance
  2. Mixer
  3. Heater
  4. Extruder
  5. Moulding machine for chewing gum (e.g., stainless steel popsicle mould, plastic basket injection mould, injection plastic air purifier mould, launch mould and die/tooling, etc.)
  6. Kneading machine/rollers
  7. Cutter

Equipment for quality control and/or performance tests e.g., equipment for testing the content and release rate of active ingredient (dissolution test), friability, hardness, stability, etc.

Production techniques in medicated chewing gum Formulation

Medicated chewing gums are manufactured using any of the following methods

  • Conventional melting Process/ kettle fusion manufacturing method
  • Freezing, grinding and tabletting Method.
  • Direct Compression Method




1. Conventional melting process/ kettle fusion manufacturing method

Most chewing gums are made using the conventional gum process. In this method, the gum base is melted or softened at about 60 oC after which it is placed in a kettle or Z-blade mixer to which active ingredient(s), and other excipients are added at a defined time to ensure a homogenous formulation. The gum is sent to a series of rollers (kneading machine) that form it into a thin, wide ribbon. During this process, a light coating of finely divided sugar or sugar substitute can be added to keep the gum away from sticking and to enhance any added flavour. The gum is then cooled for up to 48 hours in a carefully controlled room. This allows the gum to set properly. Finally, the gum is cut to the desired size and packaged as unit doses.

Note: Components of the gum base can also be added to the mixer in a solid form and are melted or softened through heating from the jacket of the kettle or Z-blade mixer.

Limitations of conventional melting process

  1. The method is not suitable for formulation of thermally labile drugs because of the heating process involved.
  2. The technology is not so easily adaptable to incorporate the stringent manufacturing conditions required for production of pharmaceutical dosage forms.
  3. Lack of precise form, shape or weight of dosage form.
  4. Melting and mixing of highly viscous gum mass make controlling of accuracy and uniformity of drug dose difficult.
  5. Grinding and compression of gums is usually difficult to achieve due to high moisture content (2 – 8 %).

2. Freezing, grinding and tabletting Method

This method has been developed with an attempt to lower the moisture content and alleviate the problems encountered in conventional method. Using a freezer apparatus, the gum base is cooled to a temperature (typically 15 °C or lower) at which the composition is sufficiently brittle and would remain brittle during the subsequent grinding step without adhesion to the grinding equipment.  The gum base can also be cooled using coolants like liquid nitrogen, hydrocarbon slush, or solid carbon dioxide. The refrigerated/cooled composition is then crushed or pulverized with a cutter or grinding apparatus to obtain minute particles of finely ground particles of the composition. The cooling and grinding steps can be combined by cooling the grinding apparatus. After the grinding step, the coolant (if used) is allowed to evaporate and disappear from the chewing gum composition. The minute particles may be coated with edible substances or premixed with powdery materials in a suitable blender such as sigma mill or a high shear mixer. For tabletization, compressing punches may be needed but an anti-adherent agent should be added to prevent sticking of finely ground particles/ granules on the punch faces.

Limitations of freezing, grinding and tabletting method of manufacturing MCG

3. Direct Compression Method

This cost-effective method involves direct compression of tailored gum base powder or granulates mixed with active ingredient and other needed ingredients into a gum tablet using conventional tablet press. As the heating process involved in the conventional methods may constrain its use with thermally labile drugs, directly compressible, free-flowing powdered gums such as Pharmagum (SPI Pharma) and MedGuniBase (Gumbase Co) were proposed to simplify the process.

Pharmagum® is commercially available in three grades namely S, M and C. Pharmagum® M has 50% greater gum base compared to Pharmagum® S which primarily contains gum base and sorbitol. Pharmagum® M contains gum base, mannitol and Isomalt.

MCGs formed by direct compression method are 10 times harder and crumble when pressure is applied resulting in faster release than MCGs formed by kettle fusion manufacturing method.

Some important formulation aspect

  1. Increased amount of softeners 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. Sustained drug delivery system can be achieved by binding a solid system of lipophilic active substance to cation exchange resin.
  4. Release of active ingredient from MCGs can be modified or controlled using microencapsulation or agglomerations methods.




Quality control test for medicated chewing gum

In addition to basic product quality tests (identification, assay, uniformity of content and mass), additional tests specific to the product may be performed to ensure good quality. These may include, for example, texture analysis, product feel and consistency, evaluation of flavours and sweeteners, tests for coatings, impurities, water content etc. As USP does not contain a compendial apparatus for evaluating performance of medicated chewing gums in many cases product performance data are generated by apparatus developed by drug product manufacturers and is not contained in the public monograph. However, when combined with basic product quality tests, performance test serves as a rugged and robust test to ensure the quality of finished products.

Read Also: Quality Control Tests for Tablets

Drug Release from medicated chewing gum

Drug release test is one of the quality performance tests necessary for assessing medicated chewing gums. Due to the complexity of the release mechanisms involved in medicated chewing gum, researchers proposed minimal requirements for experimental settings with respect to the site of release and absorption. The performance tests, however, must be able to detect the influence of critical manufacturing variables, discriminate between different degrees of product performance, and to some extent, describe the biopharmaceutical quality of finished products. Besides the product quality tests, the drug release tests can provide useful information about the characteristics of the product itself, which includes but is not limited to the influence of the composition of the gum and other excipients on drug release, a main tool required primarily during product screening and development, and to some extent the product performance in vivo. The European Pharmacopoeia (Ph. Eur.) has adopted an apparatus to determine the release rate from chewing gums formulations. The basic principle is a simple masticatory movement employed to simulate the chewing action on a piece of gum placed in a small chewing chamber containing a known volume of buffer solution are given temperature. The drug release rate is influenced by the chewing rate and angle which provides the necessary shear force to expose new gum surfaces and is requisite for further drug release. For treatment of local oral conditions, a release period of less than 1 hour is desirable, but a faster rate may be required if a rapid onset is required for systemically absorbed formulation.

Factors affecting drug release from medicated chewing gum

These include:

  1. Physicochemical properties of the drug (e.g., aqueous solubility, lipid solubility, pKa value, distribution between gum-saliva).
  2. The gum properties (i.e., composition, mass, texture).
  3. Method of manufacture of the product.
  4. Chew-related factors, including rate and frequency.

As a general rule, under sink conditions, the rate at which the drug is released is directly proportional to the chewing frequency and aqueous solubility of the drug substance and is indirectly proportional to the mass of the gum base.

Examples of Chewing gum

  • Aspergum – Aspirin (Heritage)
  • Nicorette – Nicotine (GlaxoSmithKline)
  • Nicotinell – Nicotine (Novartis Consumer Health)
  • NiQuitin CQ – Nicotine (GlaxoSmithKline)
  • Fluorette – Fluoride (Fertin Pharma A/S)
  • Vitaflo CHX – chlorhexidine (Fertin Pharma A/S)
  • Stay Alert – Caffeine (Stay Alert Safety Service, Inc.)
  • Travel – Dimenhydrinate (Astra Medica)



Advantages of medicated chewing gums

  • Convenient – promoting higher compliance.
  • Increased rate of effectiveness rather than other oral delivery systems.
  • The treatment can, if required, be terminated at any time.
  • Reduced risk of overdosing while it’s whole swallowed.
  • Does not requires water to swallow. Hence can be taken anywhere.
  • Protection of the susceptible drugs contained from chemical or enzymatic attack in gastrointestinal (GI) tract.
  • Gum does not reach the stomach. Hence gastrointestinal (GI) tract suffers less from the effects of excipients.
  • Can be used for both systemic and local drug delivery.
  • Highly acceptable by children and teenagers.
  • Low first-pass effect so reduced dose is formulated in chewing gum compared to other oral delivery systems.
  • Good for rapid delivery.
  • Fewer side effects due to avoidance of high plasma peak concentration and the promotion of controlled-release of the drug.
  • Good stability against light, oxygen, and moisture.
  • Reduced pains and difficulties in swallowing following tonsillectomy.
  • Annihilation of xerostomia and help tasting and swallowing in people with dry mouth.
  • Improving work performance and cognitive function.
  • Decreases ear discomfort when flying.
  • Fast bowel recovery after GI surgery.
  • Stimulating alertness through increased blood flow to the brain.
  • Help reduce food cravings.
  • Relaxes and eases tension.
  • Freshens the breath.

Disadvantages of medicated chewing gum

  • Disappearing of drug in the oral cavity following salivary dilution.
  • Short time of administration due to eating, speaking and drinking.
  • Different release profiles because of chewing style differences.
  • Allergic reaction to artificial sweeteners, flavourants and colourants.
  • Continuous stress on jaws that may cause temporomandibular joint disorder.
  • Stomach irritations, aches, gastric ulcer through continuous swallowing of saliva.
  • Prolong chewing on gum may also result in pain in facial muscles and earache in children.
  • Teeth decay through being coated by sugar.
  • Masseter problems.
  • Presence of sorbitol in medicated chewing gum formulation may cause diarrhoea and flatulence.
  • Getting choked by swallowing gum in under-aged children.




Reference

  • Aslani, A. and Rostami, F. (2015). Medicated Chewing Gum, A Novel Drug Delivery System. Journal of Research in Medical Sciences, 20(4): 403-411.
  • Council of Europe (2010) Europe pharmacopoeia, 6th edn. The European Directorate for The Quality of Medicine & Health Care, Strasbourg, France.
  • Gad, S. (2008). Pharmaceutical Manufacturing Handbook: Production and Processes. New Jersey: John Wiley & Sons, Inc.
  • http://www.dissolutiontech.com/DTresour/201008Articles/DT201008_A02.pdf
  • Mbah, C. (2015). Lecture on Personal Collection of Mbah, University of Nigeria, Nsukka, Enugu State.
  • Rathbone, J., Hadgraft, J. Roberts, M. and Lane, M. (2008). Modified-Release Drug Delivery Technology (2nd). New York: Informa Healthcare USA, Inc.
  • Semwal, R., Sewwal, D. and Badoni, R. (2010). Chewing Gum: A Novel Approach for Drug Delivery. The Journal of Applied Research. 10(3): 124-132.
  • Shah, K. and Menta, T. (2014). Medicated Chewing Gum – A Mobile Oral Drug Delivery System. International Journal of PharmTech Research. 6(1):35-48.

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