Medicated Chewing Gums - A Novel Option

Runwal  A. V.

Chewing gums are mobile drug delivery systems. It is a potentially useful means of administering drugs either locally or systemically via, the oral cavity.

The medicated chewing gum has through the years gained increasing acceptance as a drug delivery system. Several ingredients are now incorporated in medicated chewing gum, e.g. Fluoride for prophylaxis of dental caries, chlorhexidine as local disinfectant, nicotine for smoking cessation, aspirin as an analgesic, and caffeine as a stay alert preparation. Children in particular may consider chewing gum as more preferred method of drug administration compared with oral liquids or tablets. The use of medicated chewing gum is feasible as al local treatment of diseases of the oral cavity as well as treatment of systemic conditions.

Medicated chewing gum consists of a masticatory gum core with a coating that can be a film of polymers, waxes, sweeteners, sugar, flavors or colors. The pharmacologically active ingredients can be present in the core, in the coating or in both. Chewing gum today is gaining consideration as a “vehicle” or a “delivery system” to administer active principles that can improve health and nutrition but it’s potential as an “Alternative drug delivery system” has not been yet fully discovered and exploited. US market accounts for approx. 50% of world market for medicated chewing gums.

Advantages

·It is convenient to administer – anywhere, anytime, doesn’t require water.

·As a delivery systemic administration of drug via the oral mucosa it has the potential to overcome the problems of short lived action and variations in drug release and retention times.

·It may prove to be particularly suitable for the systemic delivery of drugs, which are susceptible to metabolism in the gut wall or liver. 

·The treatment can, if required, be terminated at any time.

· In addition, the drugs that are released from chewing gum and swallowed, will be introduced in the gastrointestinal tract either dissolved or suspended in saliva and thus will be present in a readily bioavailable form.

Dosage Form: - Chewing Gum Formulation.

Materials: -

The characteristic component of all Chewing Gums is the gum base. Other component added to Chewing Gums typically includes sweetening agents, flavoring agents and aromatics. In medicated Chewing Gum active drug is incorporated.

· Composition of Gum base: - A gum base comprises of a complex mixture of elastomers, natural of synthetic resins, fats, emulsifiers, waxes, antioxidants, fillers and flavoring agents.

·Elastomers:- they provide elasticity and cohesion to the chewing gum. Synthetic elastomers like polyisobutylene and butyl rubber are used.

·Resins: - they serve two functions. One, as mastication substance and other as binding agent between elastomers and fillers they contribute to the balance between the properties of elasticity and plasticity. Glycerol esters from pine resins are examples of natural resins. Synthetic resin polyvinyl acetate can be used. It reduces the tendency of the gum to adhere to the teeth (detackifier) and to be divided into pieces during chewing. It has only a slight taste, its stability is good and it is available in range of different molecular weights.

·Emulsifiers and fats: these are used to soften the mixture and give the required chewing consistency and mouth feel. Emulsifiers promote the uptake of saliva into the chewing gum during mastication. Monoglycerides, diglycerides and partly hardened vegetable and animal fat are examples.

·Antioxidants: they may be added to protect the gum base and flavors from oxidation. Ascorbic acid, tocopherol, butylhdroxytoluene have been used.

·Fillers: they provide the right texture for the gum base. Talc, calcium carbonate can be used.

Note: Requirements of drug candidate for Chewing Gum.

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 mcm to avoid unpleasant gritty feeling during chewing.

Methods:

The manufacturing processes begin by softening the gum base at a temperature of 50 to 60 in a mixer using slow turning blades. Sweeteners and syrups are then added. Syrups keep gum moist and help the sugar sugar combine easily with gumbase. Flavors and softeners are then added 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 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. This carpet is rolled out to right thickness by series of rollers before it is scored into single pieces. The chewing gum is then moved into a conditioning room where temperature and humidity are carefully controlled. This gives the product a good durability. After a few days of maturing the gum is ready for coating.

Time of drug incorporation:generally the drug should be added into the gum base itself; however it is possible to add the drug during coating process if the drug is unstable under any of the conditions employed during the manufacturing process. Some gum manufacturers have developed a granulation and compression method similar to that used in manufacture of tablets.

Direct Compression Chewing Gum: Pharmagum is a compatible gum system that has been developed by SPI pharma. Pharmagum is a mixture of polyols and of sugar with gum base. It is a free flowing powder, which is directly compressible. This gum is manufactured under cGMP conditions and complies with food chemicals. 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.

Parameters:

a) Drug release:

The need for and value of in-vitro drug release testing is well established for a range of dosage forms, however standard dissolution apparatus is not suitable for monitoring release of drug from chewing gums as the action of chewing is essential, by providing a renewable surface for drug release after Chewing Gum action. The release of substances from chewing gum during mastication can be studied by employing a panel of tasters and chew-out studies. During the mastication process, the medication contained within the gum product should be released in to the saliva and is either absorbed through oral mucosa or swallowed and absorbed through the gastrointestinal tract. The chewed gum can them be removed and analyzed for the residual drug substance while pharmacokinetics can be determined from blood samples. Disadvantages of Chewing Gum out studies include requirement for human volunteers, lack of Chewing control and variations in the flow and composition of subject’s saliva. There is no official method to evaluate the release of drug from chewing gum, but several methods have been reported.

There are two apparatus for studying release from chewing gum –

1)“MASTICATOR M 36”

2)Instrument for In-vitro dissolution of medicated chewing gums 6-cell chewing apparatus.

1)“MASTICATOR M 36”:

Christrup and Moller’s experiences prompted them to design a new chewing gum machine. This machine consists of a temperature-controlled reservoir for dissolution medium and two pistons. 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 starting point. To perform, 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 quantity of drug released is determined. The cycle rate (chewing rate) is usually set at 60 per minute, and 20 mL of dissolution media equilibrated to 37° are typical volumes and temperatures of dissolution media.

2)Instrument for In-vitro dissolution of medicated chewing gums 6-cell chewing apparatus:

The apparatus designed by Christrup and Moller has been developed further to allow experiments to be performed which allow six pieces of chewing gum to be evaluated art the same time. In addition to the two horizontal pistons the chewing chambers are supplied with vertical piston working staggered to the e horizontal. This ensures that the gum is always positioned in the right place during the mastication process. One cycle of the piston consist of t one upward and one downward stroke, with cycle frequencies of 7.5-30 every minute. Simultaneously, the plunger consistently rotates during the experiments at 10-40 rpm and a cycle frequency of 30 cycle per minute were found to give release rates similar tc those observed in vivo. When comparing the difference mastication devices the one developed by the Rider et al seems to operate well but more data is needed. The apparatus of Christrup and Moller has bee used in many studies with different formulations of chewing gums containing drug of wide range of aqueous solubilities. In 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. The fact that six pieces of chewing gum can be examined at the same time is advantageous as it provides more results at a faster data obtained with this apparatus would be expected to be more reproducible than the results obtained with the original apparatus developed buy Christrup and Moller because of the additional vertical piston that maintains the gum in the correct position.

This is the world’s only commercially available instrument for in-vitro dissolution of chewing gums. Leader in Nicotine gums, Nicoratte®, is registered by FDA and all over the world with dissolution data from this chewing apparatus does not yet have compendial method but is familiar with this instrument.

Release of nicotine from conventional gums and from gums made using a directly compressible gum base was studied using the European Pharmacopoeia apparatus for testing of medicated chewing gums.

Factors Affecting the Release:

Several factors have been shown to affect release of drugs from chewing gum. The major determinants include the chewing time, chewing rate, aqueous solubility of the drugs, and composition of the chewing gum.

1) Chewing time and rate: a self-reporting questionnaire technique was developed to determine the length of chewing time. The mean chewing time per piece of gum was 36 min. the rate at which a subject chews gum also affects the amount of drug released. The average chewing rate is about 60 chews every minute.

2)Aqueous solubility of the Drug: Release of water soluble drug (aqueous solubility greater than 1:10 ) is, in general, about 75% or more during 5 min. of chewing and 90% or more during 15 min. of chewing at rate of 60 chews per minute. Drugs with aqueous solubility between 1:10 and 1:300 demonstrate up to 60% release during 10 minutes of chewing and between 50 to 90% when the gum is chewed for 15 min. the release of the drug, which is only slightly water-soluble, can only be expected to be small (less than 5%) even if the gum is chewed for 30 min.

3) Composition of chewing gum: the influence of gum base mass on drug release has been investigated using salicylamide as model drug. When salicylamide was incorporated into a chewing gum, which contained a relatively large percentage of gum bases, the release after 30 min. of chewing was significantly lower (25.6%) compared to a gum in which less gum base was present (52%).

Applications

·Dental care

·Oral infections

·Smoking cessation

·Antacids

·Vitamins and minerals.

·New trends.

Smoking cessation:

Nicotine gum is a form of nicotine replacement therapy (NRT), which can be double your chances of stopping smoking as compared with will power alone.

A nicotine containing chewing gum (Nicorette®, Leo) has been marketed as an aid to give up smoking. When nicotine is incorporated into ordinary gum compositions, it release occurs rapidly. Such a release profile is, however undesirable for its clinical use which requires that the release from a nicotine chewing gum formulated as smoking substitute should be uniform and last for at lease 20 min. in addition the released nicotine, should produce a “feeling of smoking” not only following absorption but also in mouth. In July a patent was taken by Lichtneckert describing tobacco alkaloids bound to a cation exchanger containing functional carboxylic or sulfonic groups. The cation exchanger used in the marketed Nicorette® chewing gum is Amberlite IRP 64M, a weak acidic methacrylic acid polymer and the nicotine complex product is referred to as nicotine polacrilex.

Safety aspects:

Difference commercial chewing gums have been shown to adhere to different degree to dentures, fillers and crowns. Over chewing causes painful jaw muscles. Chewing gum appears to offer a smaller risk of overdosing by mistake or misuse than flavored chewable tablets. Medicated chewing gums should, like other medicaments, be kept out of reach of children and it would be wise to advice people prone to allergic responses to check the flavoring and sweetening agents included in the chewing gum formulations.

References: -

1) Rider, P.H., Walker, L.A. , Wyandt, C.M., Jones, A.B.,,1992 Development and evaluation of a novel dissolution apparatus for medicated Chewing gum products. Pharm. Res. 9, 255–259.

2) Rindum, J., Holmstrup, P., Pedersen, M., Rassing, M.R., Stoltze, K., 1993.Miconazole chewing gum for treatment of chronic oral candidosis. Scand. J. Dent. Res. 101, 386–390.

3) Rowe, R.C., 2003. By gum—a buccal delivery system. Drug Discovery Today 8, 617–618.

4) Testa, E.S., 2 February 1999 . Medicated chewing gum and process for Preparing thereof. U.S. Patent 5,866,179.

5) Abelson , D.C. , Barton, J., Mandel, I.D., 1990. The effect of chewing Sorbitol-sweetened gum on salivary flow and cemental plaque pH in Subjects with low salivary flow. J. Clin. Dent. 2, 3–5.

6) Barabolak, R., Hoerman, K., Kroll, N., Record, D., 1991. Chewing gum Profiles in U.S. Population. Commun. Dent. Oral Epidemiol. 19, 125.

7) Christrup, L.L., Bonde, J., Rasmussen, S.N., Rassing, M.R., 1990. Relative bioavailability of (±) verapamil hydrochloride administered in Tablet and chewing gum. Acta Pharm. Nord. 2, 371–376.

8) Conte, U., Maggi, L., Colombo , P., La Manna, A., 1993. Multi-layered Hydrophilic matrices as constant release devices (Geomatrix®). J. Control Release 26, 39–47.

9) Dodds, M.W.J., Hsieh , S.C. , Johnson, D.A., 1991. The effect on increased mastication by daily gum chewing on salivary gland output and dental plaque acidogenicity. J. Dent. Res. 70, 1474–1478.

10) Eisenstadt, B., Cash, A.P., Bakal, I.A., 8 December 1998 . Chewing gum Containing cough suppression agent. U.S. Patent 5,846,557.

11) Chewing gum, medicated, drug release, 2002. European Pharmacopoeia, Fourth ed., pp. 227–228.

12) Dosage Forms, 2002. European Pharmacopoeia, fourth ed., p. 537.

13) Liljewall, L.R., 11 February 1992 . Apparatus for mechanical processing of a sample and a member of such an apparatus. U.S. Patent 5,087

14) Nemeth-Coslett, R., Benowitz, N.L., Robinson, N., Hennigfield, G.E.,

1988. Nicotine gum: chew rate subjective effects and plasma nicotine.

Pharmacol. Biomed. Behav. 29, 747–751.

15) Pedersen, M., Rassing, M.R., 1990. Miconazole chewing gum as a drug delivery system: application of solid dispersion technique and lecithin. Drug Dev. Ind. Pharm. 16, 2015–2030.

About Authors:-

Prof.(Ms) V.V Potnis

Asst. Professor of Pharmaceutics, , M.Pharm,Pharmaceutics, Padmashree Dr. D. Y Patil institute of Pharmaceutical Sciences & Research, Pimpri, Pune-18, M.H

Runwal A.V

Student, M.Pharm, Quality Assurance techniques (fourth sem.),Padmashree Dr. D. Y Patil institute of Pharmaceutical Sciences & Research, Pimpri, Pune-18, M.H

Lone K. D

Student, M.Pharm, Pharmaceutics (fourth sem.), Padmashree Dr. D. Y Patil institute of Pharmaceutical Sciences & Research, Pimpri, Pune-18, M.H

For Correspondence jaysingpuramitblue@yahoo.co.in