FORMULATION:Gums

A Doctor's Note for Gum?

Chewing Gum is No Longer a Sure-Fire Way to Get Kicked Out of Class

Chewing gum has been used worldwide since ancient times after man experienced the pleasure of chewing a variety of substances. One thousand years ago, the Mayan Indians chewed tree resin from the sapodilla tree in order to clean their teeth and freshen the breath.¹ Shortage of natural gum bases during World War II enhanced development of the synthetic gum bases that are used today. Medicated chewing gums are solid, single dose preparations consists of a masticatory gum core with a coating that can be a film of polymers, waxes, sweeteners, sugar, flavors or colors. The therapeutically active ingredients can be present in the core, in the coating or in both.²

Medicated chewing gum can be used as a convenient modified release drug delivery system. It is well accepted in both adults and children compared with oral liquids and tablets. Medicated chewing gum is a potentially useful means of administering drugs either locally or systemically via the oral cavity. It is currently available for pain relief, smoking cessation, motion sickness and freshening of breath. The first patent for the production of chewing gum was filed in 1869 and was issued to W. F. Semple in Ohio under U. S. Patent No. 98,304. The first medicated chewing gum "Aspergum" was launched in 1928.³This chewing gum is still available and contains acetylsalicylic acid. In 1991, chewing gum was approved as a term for pharmaceutical dosage form by the commission of European Council. However, chewing gum did not gain acceptance as a reliable drug delivery system until 1978, when nicotine chewing gum became available.

Owing to new social and behavioral trends in the modern age, such as the growing consumer health awareness and increasing attention to safety products, chewing gum has been known for its new image and potential. Today, chewing gum is considered as a convenient "vehicle" or a "delivery system" to administer active principle that can improve health and nutrition, but its potential as an "alternative drug delivery system" has not yet been fully discovered and exploited.

Merits of medicated chewing gum:

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

• Highly acceptable by children.

• Advantageous for patients with difficulty in swallowing tablets.

• Pleasant taste.

• Excellent for acute medication.

• Counteracts dry mouth through stimulation of the salivary secretion, thereby preventing candidiasis and caries.⁴

• The stomach does not suffer from direct contact with high concentrations of active principles, thus reducing the risk of intolerance of gastric mucosa.³

• Avoids first pass metabolism and thus increases the bioavailability of drugs.³

• The fraction of product reaching the stomach is conveyed by saliva delivered continuously and regularly. Duration of action is increased.

• Fast onset due to rapid release of active ingredients in buccal cavity and subsequent absorption in systemic circulation.⁴

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

Demerits of medicated chewing gum:

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

• 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.¹

• Prolong chewing on gum may result in pain in facial muscles and ear ache in children.⁶

• Additives in gum like a flavouring agent Cinnamon can cause ulcers in the oral cavity and licorice can cause hypertension.

• Chlorhexidine oromucosal application is limited to short term use because of its unpleasant taste and staining properties to teeth and tongue.⁷

Components of Medicated Chewing Gum

The characteristic component of all chewing gum is the gum base. It may be water insoluble gum base or water-soluble gum base. The basic raw material for all chewing gum is natural gum Chicle, obtained from the sapodilla tree.¹ Chicle is very expensive and difficult to procure, therefore other natural gum or synthetic materials like polyvinylacetate and similar polymers can be used as gum base. In medicated chewing gum, a therapeutic agent may be present in the core or coating or in both. The proportion may vary from 0.5-30 percent of final gum weight. Other components added to chewing gum typically include sweeteners, coloring agents, flavors and anti-oxidants are listed in Table 1.

Manufacturing of Medicated Chewing Gum

To successfully manufacture chewing gum, the ingredient must be added at the right time and must not be mixed for too long or too short of a period. The warm mass from mixers passes onto slow moving cooling belts, which are bathed in currents of cool air. The mass then moves to the rolling plant where the gum mass is extruded into the carpet of gum that is rolled out to proper thickness. The chewing gum is then moved into a conditioning room where temperature and humidity are carefully controlled. If a drug is unstable during any of the conditions employed in the manufacturing process, it should be added into the gum base during the coating process. Some gum manufacturers have developed a granulation and compression method similar to that used in manufacturing of tablets.⁹Gum is manufactured under cGMP conditions and complies with Codex specifications as well as with FDA, so they can be considered as safe. Today, direct compression chewing gum can be directly compressed on a traditional tabletting machine, thus enabling rapid and low cost development of a gum delivery system.¹⁰

Problems Occurred During Manufacturing of Chewing Gum

• Generally the chewing gum will jam the grinding machine, sticking to blades, screens and other surfaces if the moisture level is not controlled.

• Another problem associated with the above methods is that the gum base is heated to a fluid mass to facilitate mixing of other ingredients. Such elevated temperatures can cause degradation of heat sensitive compounds, including active agents and flavors.

• In manufacturing of chewing gum, sometimes organic solvents are used to dissolve the active agents. It is difficult to eliminate these organic solvents from the final product and may present certain health risks if even trace amounts remain in the final dosage forms.

• Water can also be utilized in gum preparations, but it is difficult to eliminate at low temperature. Heating the gum mass to eliminate water is not advisable because the gum will then become stickier, which makes handling difficult and interferes with large-scale production.

Drug Release Study of Medicated Chewing Gum

In vitro Apparatus

A number of devices to mimic the chewing action have been reported. An apparatus for in vitro drug release testing of medicated chewing gums has been developed by Kvist C et al.¹¹ They have studied the effect on chewing surfaces, twisting movements of surfaces and temperature of the test medium on the release rate of drug from MCG.

Another novel dissolution apparatus has been developed for MCG by Rider JN et al.¹² The apparatus consists of a 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 Rider JN et al.

The apparatus designed by Christrup and Moller has been further developed to allow experiments to be performed that allow six pieces of chewing gum to be evaluated at the same time (Figure 1). This apparatus has been used in many studies with different formulations of chewing gums containing drugs of a wide range of aqueous solubilities.¹³In general, the results have shown a high correlation between in vitro and in vivo release data. The latest device that has been developed seems promising, efficient and easy to operate.

Fig. 1: Chewing apparatus DRT 6

In 2000, the European Pharmacopoeia published a monograph describing a suitable apparatus for studying the in vitro release of drug substances from chewing gums.¹⁴ This machine consists of a temperature controlled reservoir for dissolution medium and two electronically-controlled horizontal pistons driven by compressed air (Figure1). During one chewing cycle, the piston (one on each side), move towards each other. When they meet, they press the chewing gum between them and then make a twisting movement before returning to the starting point. To perform a drug release test, a known quantity of chewing gum is placed in the dissolution medium reservoir, and pressing and twisting forces are transmitted to the gum via the pistons. At specified time intervals, a sample is removed from the reservoir and a quantity of drug released is determined. The temperature of the chamber can be maintained at 37�0.5^o C and the cycle rate (chewing rate) is usually set at 60 stokes per minutes. The European Pharmacopoeia recommends using 20 ml of unspecified buffer (with a pH close to 6) in a chewing chamber of 40 ml.

Pharmaceutical Applications

Dental Caries

Prevention and cure of oral diseases are obvious targets for chewing gum formulations. Sugar-free chewing gum is known to be beneficial to dental health. It has been shown that use of sugar-free chewing gum after meals re-elevates plaque pH. Low plaque pH plays an important role in the development of dental caries. Therefore, in caries prevention programs, sugar-free chewing gum is recommended after meals and snacks as a supplement to tooth brushing.¹⁵ Perfetti Van Melle India Private Limited, has launched Happydent Protex, a specially formulated sugar-free chewing gum that helps prevent tooth decay. The gum has a fresh mint flavor and contains xylitol as one of the ingredients.¹⁶

Chlorhexidine chewing gum can be used for alleviations of gingivitis, periodontitis and other oral infections. The anti-plaque effect of chlorhexidine is well known. Furthermore, chlorhexidine in chewing gum formulations means less staining of the teeth and is more convenient to use than a chlorhexidine mouth rinse. The chlorhexidine released by chewing is distributed evenly in the oral cavity and is present there for a prolonged time.¹⁷ Fluoride containing chewing gum is used in prevention of dental caries in children in fluoride deficient areas, in adults with a high incidence of caries and in patients with xerostomia.¹⁸ The antifungal drug Miconazole is used for treatment of oral candidiasis. Miconazole chewing gum is more efficient than the Miconazole oral gel in the treatment of fungal infections in the mouth. Furthermore, patients preferred chewing gum to oral gel due to convenience and fewer side effects.¹⁹

Fig. 2: Schematic diagram of the chewing chamber of in vitro chewing apparatus used

Smoking Cessation

Chewing gum formulation containing nicotine, lobeline and silver acetate have been clinically tested as aids to smoking cessation. Nicotine is a therapeutic agent intended to help smokers break the psychological habit of smoking by reducing the nicotine withdrawal symptoms normally experienced when smoking is stopped. A chewing gum containing nicotine (Nicorette) has been marketed as an aid to give up smoking. When nicotine is incorporated into ordinary gum compositions, its release occurs rapidly. A pharmacokinetics study of nicotine chewing gum indicated that approximately 80 percent of the nicotine released from the chewing gum was absorbed through buccal route.²⁰

Obesity

Several chewing gum formulations containing caffeine, guarana or chromium are available. Caffeine and guaran stimulate lipolysis and have a thermogenic effect (increased energy expenditure) and reduced feeling of hunger. Chromium is claimed to reduce the carving for food due to an improved blood glucose balance. Chewing gum has been proven efficient in treatment involving instant raving and "oral habit." Hence, there is a rationale for administering weight reducing active substance in a chewing gum formulation.

Pain

Analgesic chewing gum, Aspergum, which is chewing gum containing aspirin, treats fever, pain, inflammation and reduces the blood's ability to clot. The bioavailability of aspirin in a chewing gum and tablet formulation has been studied. Absorption of aspirin from a chewing gum formulation was shown to be faster than the tablet. Consequently, aspirin chewing gum may provide faster pain relief.²¹ A chewing gum formulation may also be useful in the treatment of acute, strong pain. Bioavailability of methadone from a chewing gum formulation has been compared to a tablet formulation. There was no significant difference in the bioavailability of the two formulations.²² The substance abuse problem with methadone tablets could be considerably reduced by formulating methadone in a chewing gum, as the active substance can only be released by chewing.

Motion Sickness

Chewing gum as a drug delivery system offers convenience in the treatment/prevention of motion sickness and nausea. Medical chewing gum containing dimenhydrinate for motion sickness is already on the market, however, active substances like scopolamine, metoclopramide, ondansetron and dolasetron may be candidates for a chewing gum formulation for the treatment/prevention of motion sickness and nausea.

Miscellaneous Application

Effervescent chewing gum is an oral hygiene preparation that is plaque disrupting in the form of a chewing gum. The chewing gum comprises a core containing a carbonate or/and bicarbonate, which is surrounded by a coating that contains an encapsulated edible acid. Upon mastication, the chewing gum effervesces, thus promoting the cleansing and breath freshening properties of the preparation.²³ Antacid containing gum may even outshine antacid tablets. Researchers suggested chewing antacid containing gum to those patients who are suffering heartburn-like problem. Sodium bicarbonate and calcium carbonate (surpass) containing medicated chewing gums are available in the market.²⁴ Several chewing gum formulations containing calcium are available in the market. Adolescents constitute a potential target group for calcium chewing gum, as the calcium intake in young people is often very low. Calcium chewing gum with a pleasant flavor is attractive and convenient to table.

Vitamin C containing chewing gum has been evaluated in the "safe for teeth test" and was found safe. Allergy, diabetes, anxiety, dyspepsia, osteoporosis and cough and cold are all indications for which chewing gum as a drug delivery system could be beneficial. Chewing gum containing Noscapine was formulated as an antitussive preparation. Researchers found it is more effective than tablets and syrup.²⁵

Conclusion

It is obvious that chewing gum can be used as a carrier for vast categories of drugs where drugs are released over a longer period of time than those delivery systems conventionally used in oral cavity. Chewing gum is an excellent drug delivery system for self-medication, as it is convenient and can be administer discreetly, without water at any time. It offers several advantages compared to chewable tablets, lozenges and other related formulations hence, in the coming years, it is very likely that chewing gum will become a common drug delivery system. �

References:

1.Jacobsen J, Christrup LL, Jensen NH, Am. J. Drug Deliv. 2004; 2(2):75-88.

2.http://www.fertin.com/fileadmin/pdf/Chewing_gum_as_a_DDS.pdf.

3.Conway B, The Drug Delivery Companies Report Autumn/Winter. 2003;33-35.

4.Morjaria Y, Irwin WJ, Barnett PX, Chan RS, and Conway BR, Dissolution Technologies. 2004; 5:12-15.

5.Munksgaard EC, Nolte J, Kristensen K, Am. J. Dent. 1995;8(3):137-139.

6.Weil AT, Am. J. Drug Alcohol Abuse. 1978;5(1): 75-86.

7.Addy M, Roberts WR, J. Clin. Periodontol. 1981;8(3):220-230.

8.Zyck DJ, Greenberg; MJ, Barkalow DG, Marske SW, Schnell PG, Mazzone P, US Patent 6645535;2003.

9.Zibell S, K. Broderick, Eur. Patent. 0492980;1992.

10.Jacob P. et. al., Technical Bulletin. 2003.

11.Kvist C, Anderson S-B, Fors S, Int. J. of Pharmaceutics. 1999;189:57-65.

12.Rider JN. Brunson EL, Pharm. Res. 1992;9:255-260.

13.LL Christrup, N Moller, Arch. Pharm. Chem. Sci. Edu. 1986;14:30-36.

14.European Pharmacopoeia 4th Edition-2002, General Chapter 2.9.25. PP 2227-228, Directorate for the quality of medicines of the council of Europe, Strasbourg. 2001.

15.Imfeld T, Crit. Rev. Oral Biol. Med. 1999;10:405-419.

16.Edgar W, Br. Dent. J. 1998;184(1):29-32.

17.Glavind L, Karring T, J. Dent. Res. 1992;72:584.

18.Ekstrand J, Edwardson S, Scand. J. Dent. Res. 1985;93:309.

19.Rindum J, Holmstrup P, Scand. J. Dent. Res. 1993;101:386.

20.WW Lee, Pharm. Tech. 2001;2:1-11.

21.Woodford W, Lesko L, J. Pharm. Sci. 1981;70:1341-1343.

22.Christrup, LL. et al, Acta. Pharm. Nord. 1990;2:83-88.

23.Lombardy, Charles, US Patent 6235318;2001.

24.Alan T, Heartburn/GERD treatment. The Analyst. 2005.

25.Jensen LN, Christrup LL, Acta Pharm. Nord. 1991;3(4):219-222.