medicated chewing gum by geethapink

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									Medicated Chewing Gum (MCG) as Drug Delivery System

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Introduction
The chewing of gum is a well accepted and frequently undertaken activity in both adults and children. Commercially available medicated chewing gums are indicated for: pain relief smoking cessation travel illness freshening breath prevention of caries Vitamin and mineral supplementation

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Introduction
Are solid, single dose preparations with a base consisting mainly of gum that are intended to be chewed but not swallowed. They contain one or more active substances which are released by chewing and are intended to be used for local treatment of mouth diseases or systemic delivery after absorption through the buccal mucosa (Ref: EP, 5th edition, 2004). Represents the newest system with potential uses in pharmaceuticals, over the counter medicines and neutraceuticals. The drugs intended to act in oral cavity often have low water/saliva solubility and chewing gum constitute a valuable delivery system for such drugs.
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Historical Aspect
1848: first manufacture of chewing gum sticks 1869: first patent for chewing gum by a dentist, Semple from Ohio 1879: pepsin powder and chewing gum blended together to aid digestion 1880: The first fruit flavoured chewing gum was marketed by William Wrigley and “Lotta” and “Vassar” in 1892 and afterwards spearmint flavoured gum called “Wrigley’s Spearmint”. 1899: “Dentyne” was marketed for dental cleansing

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Historical Aspect (Contd.)
1928: “Aspergum” containing aspirin was mfd. and is still on the market today. Nowadays, chewing gums are marketed worldwide and in most countries is accepted as harmless practice2. 2. Rassing et al. Medicated Chewing Gum, MRDDS, Marcel Dekker, 419-429

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Advantages of Medicated Chewing Gum
Does not require water to swallow. Hence can be taken anywhere. Excellent for acute medication. Counteracts dry mouth, prevents candidiasis and caries. Stomach does not suffer from direct contact with high concentrations of actives, thus reducing the risk of intolerance of gastric mucosa. Avoids first pass metabolism and thus increases the bioavailability of drugs
1. Rassing et al. Oral Mucosal Drug Delivery Systems, Marcel Dekker, 319-357.

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Components of Medicated Chewing Gum
Component
Drug Gum base Bulk sweetening agent Flavouring agents Colour Softeners

Concentration (%)
Approximately upto 50% 20-40% 30-75% 1-5% <1% 1-5%

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Gum Base Components
Gum base component Elastomer Function Example Impart elasticity and •Polyisobutylene cohesion •Butyl rubber •Styrenebutadiene (used in bubble gum) •Mastication substances •Binding agent between elastomers and fillers Soften the mixture Protect gum and flavours oxidation To provide texture •Natural: Glycol esters from pine resin •Polyglycerol esters •Synthetic: polyvinyl acetate (also detackifier i.e. reduces tendency to adhere to teeth. •Fat: Monoglycerides •Emulsifier: microcrystalline wax

Resins

Emulsifiers and fats Antioxidants

base Ascorbic acid, tocopherol, BHA, BHT from right Talc (for sour ing. due to resistance), calcium carbonate its acid

Fillers

3. (PCT Int. Appl. 96/13986/7)

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The Manufacturing Process
Different methods are employed for the manufacturing of chewing gums: Conventional method a) Softening of gum base at a temp. of 50-70°C b) Addition of corn syrup or glucose syrup c) Addition of softeners, flavours, colours and drug d) Mixing and warm mass extrusion e) Cutting into pieces and storage in a room with the controlled humidity and temperature f) Coating: drug may also be incorporated in coating membrane
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The Manufacturing Process
Cooling, Grinding and Tabletting Method a) The CG composition (base) is cooled to a temperature at which the composition is sufficiently brittle and would remain brittle during the subsequent grinding step without adhesion to the grinding apparatus. b) Generally the temperatures of the refrigerated mixture is around –15°C or lower. Amongst the various coolants like liquid nitrogen, hydrocarbon slush use of solid carbon dioxide is preferred.

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The Manufacturing Process
c) The refrigerated composition is then crushed or ground to obtain minute fragments of finely ground pieces of the composition. d) After the composition is ground to a powder, the coolant can be removed by allowing the coolant to evaporate. e) Once the coolant has been removed from the powder, the powder can be mixed with other ingredients such as binders, lubricants, coating agents, sweeteners etc, all of which are compatible with the components of the chewing gum base in a suitable blender such as sigma mill or a high shear mixer.
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The Manufacturing Process
f) The granules so obtained can be mixed with antiadherents like talc. The mixture can be blended in a V type blender, screened & staged for compression. Compression can be carried out by any conventional process like punching. Use of directly compressible excipients such as Pharmagum. chewing gum

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Drug release study from Chewing gum
The first monograph on medicated chewing gum was published in EP in 1998. In the year 2000 the first monograph on a principle chewing apparatus and a procedure for the determination of drug release from medicated chewing gum was published in EP.

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In Vitro Assessment of Chewing GumApparatus for Assessing Drug Release from Chewing Gum
The European Pharmacopoeia has developed a 3-piston apparatus, which in essence “chews” the gum at a rate of 60 cycles/min in a test medium with pH 6.0 at 37°C4. 4. British 2007 Pharmacopoeia

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In Vitro Assessment of Chewing GumApparatus for Assessing Drug Release from Chewing Gum
Christrup and Moller1 designed a new chewing machine which is shown in following figure. The machine consists of a temperature controlled reservoir for the dissolution medium and two horizontal pistons driven by compressed air.

1.Rassing et al. Oral Mucosal Drug Delivery Systems, Marcel Dekker, 319-357. 15

In Vitro Assessment of Chewing GumApparatus for Assessing Drug Release from Chewing Gum
During one chewing cycle, the pistons, one on each side, move towards each other (figure). When they meet they press the chewing gum between them and then make a twisting movement before returning to the starting point. The cycle rate is usually set at 60 stokes per minute, and temp. at 37°C.

A cross sectional diagram of the release chamber of the chewing machine constructed by Christup and Moller, 1-reservoir, 2-piston, 3dissolution medium reservoir lid
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In Vitro Assessment of Chewing GumApparatus for Assessing Drug Release from Chewing Gum
There are several disadvantages of the in vitro drug release test apparatus described above. For instance, the chewing gum may adhere to the equipment, thus affecting its ability to imitate in vivo condition5. 5. Azarmi et al. Int. J. Pharm. 328 (2007), 12-21.

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In Vivo Assessment of Chewing GumChew-Out Method
Some researchers6,7 studied the in vivo method in which they selected volunteers to chew the medicated gum for a specified period of time (i. e. 10, 20, 30 or 40 min); followed by analyzing the residual quantity for the amount of active ingredient remaining in the gum. This method definitely warrants some scrutiny in methodology but is a prime example, which demonstrates the need of developing an appropriate in vitro test apparatus to analyze the release of medication from chewing gums.
6. 7. Yang, Z., Wang, G., Zhang, X., 2004. J. Pharm. Sci., 293-299. Na, D. H., Faraj, J., Capan, Y., Leung, K. P., DeLuca, P. P., 2005, J. Control. Release, 107, 122-130.
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Factors Affecting Release of Drug from Chewing Gum
1. 2. Physicochemical Properties of the Drug e. g. aqueous solubility Product properties e.g. composition of chewing gum, method of manufacture 3. Process of Chewing e. g. chewing time and chewing rate

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Factors Affecting Release- Aqueous solubility of the Drug
Aqueous Solubility >1:10 Chewing Time 5 min 15 min 1:10 to 1: 300 10 min 15 min Slightly soluble 30 min (1:1000) Chewing Rate 60/min 60/min 60/min 60/min 60/min Percent Drug Release > 75% > 90% > 65% 50 to 90% Less 10% than

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Factors Affecting Release Composition of Chewing gum
The influence of gum base mass on drug release has been investigated using salicylamide as a model substance*. When salicylamide was incorporated into a chewing gum which contained a relatively large percentage of gum base the release of gum base was significantly lower (25.6%) compared to a gum in which less gum base was present (52.0%).
* Rassing et al. Oral Mucosal Drug Delivery Systems, Marcel Dekker, 319-357.

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Factors Affecting Release- Formulation and Manufacturing factors
The use of a more hydrophobic gum base as opposed to a hydrophilic gum base often results in a decreased release rate of any incorporated drug. Drug release from chewing gum can be modified a) by addition of substances to the gum base which exhibit different lipophilic or hydrophilic characteristics, b) by modifying the physical characteristics of the incorporated drug. E.g. Release of micronized salicylamide from chewing gum was doubled than coarse salicylamide.
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Factors Affecting Release- Chewing Time and Chewing Rate
The time and rate at which a subject chews gum also affects the amount of drug released. The average chewing rate is about 60 chews every minute for 30 minutes. The release of nicotine from Nicorette® chewed at different rates has been investigated. A chewing rate of 1 chew every second, gave a significantly (P<0.05) higher release than a chewing rate of 1 chew every 8 seconds*.
* Rassing et al. Oral Mucosal Drug Delivery Systems, Marcel Dekker, 319-357.
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Methods of Increasing Drug Release from Chewing gum
Many of the drugs used today are lipophilic in nature. Lipophilic drugs are partially soluble in gum base. Consequently they exhibit a slow and incomplete release rate from chewing gum. For such drugs it may be necessary to develop methods which increase the rate and extent of release from chewing gum.

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Increasing Drug Release- Coating with Hydrophilic Gum
Witzel et al8 coated particles of finely divided nystatin with Arabic gum. When uncoated drug was incorporated into chewing gum a release of only 4% was observed in vivo in a panel of 5 subjects. The amount increased to 24% when coated drug was incorporated into gum.

8. US Patent 4238475

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Increasing Drug ReleaseSolubilizing Agents
Anderson et al.9 studied the effect of adding various nonionic surfactants on the release of nystatin (slightly water soluble) from chewing gum. The solubilizing agents investigated were Cremophor RH 40 (polyoxyethylene trihydroxy stearate), Tween 60 and Panodan AB 90 (monoglyceride diacetyl tartrate). Nystatin and the solubilising agents were mixed together in a ratio of 1:1 prior to incorporation into chewing gum base.
9. Anderson et al., DDIP,16,1985 (1990)
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Increasing Drug ReleaseSolubilizing Agents
The in vitro release rate of nystatin in the presence of each of the surfactants increased dramatically compared to a piece of gum in which nystatin was formulated on its own. The quantity of released drug was observed to be increased by a factor of 50-70 with upto 95% of the incorporated drug being released.

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Increasing Drug ReleaseSolubilizing Agents
Miconazole chewing gum co-formulated with the different anionic surfactants Panodan (diacetyl tartaric acid esters of mono-and diglycerides) and Acidan (a citric acid ester of monoglyceride) has been investigated10. A detackifying agent PEG 6000 was also included in the formulation. The in-vitro release of miconazole from chewing gum containing 5% Panodan and 5% PEG 6000 was several times higher than from chewing gum containing pure miconazole.
10. Pedersen et al., DDIP, 17, 411 (1991)
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Increasing Drug Release- Solid Dispersion
Pedersen et al11 formulated solid dispersions of miconazole using carriers like PEG 6000, PVP, xylitol and carbamide. The preparations were made either by pounding a mixture of miconazole and the carrier or by a molten or precipitation method. The solid dispersion of miconazole in PEG 6000 increased the release rate to a larger extent over the first few minutes of mastication.
11. Pedersen et al. DDIP, 16, 2015 (1990)

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Sustained release of drugs
Sustained release of drug from chewing gum is required when a) drug is intended to act locally in the oral cavity for a prolonged period b) drug can cause adverse effects if high local concentrations are allowed to build up on the mucosa Very few methods have been documented in the literature which reduce the release rate of drugs from medicated chewing gum.

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Sustained release of drugs (Contd.)
E.g. Nicorette in which nicotine is formulated as a complex bound to a cation exchange resin (Amberlite IRP 64). The release rate of nicotine from the gum can be varied by changing the amount of nicotine bound to a given quantity of cation exchanger.

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Sustained Drug Release- Drug-Ion Exchange Complex
Nicotine is a liquid with a pKa of 3.12 and 8.02. At pH 7.5, less than 30% of nicotine exists in the absorbable unionized form. When nicotine is incorporated into ordinary gum compositions, its release occurs rapidly. Such a release profile is, however, undesirable for its clinical use which requires that release from a nicotine chewing gum formulated as a smoking substitute should be uniform and last for at least 20 minutes. In addition the released nicotine should produce a “feeling of smoking” not only following absorption but also in the mouth.
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Sustained Drug Release- Drug-Ion Exchange Complex
In July 1975 a patent12 was disclosed which describes tobacco alkaloids bound to a cation exchanger containing carboxylic or sulfonic acid groups. The "feeling of smoking" is weaker, if the alkaloid is released from the gum as the base. This is due to the fact that the alkaloid is absorbed very readily at the chewing site, that is, the part of the mouth that is in direct contact with the chewing gum. Thus only a relatively small amount of the alkaloid is transported to other parts of the mouth including the throat. The throat seems to be very sensitive to nicotine.
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Sustained Drug Release- Drug-Ion Exchange Complex
If, nicotine is liberated as the nicotine cation, the absorption does not take place so quickly, thus allowing some of the nicotine to reach other parts of the buccal cavity including the throat, whereby some of the sensations of smoking are obtained, including a light burning sensation, which the smoker generally estimates in a positive way. 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 polacrilex.
12. US Patent 3901248
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Sustained Release of sweeteners and flavours
The taste of saccharin or its salts are prolonged13 by entrapment of dissolved or dispersed saccharin or its salts in hydrophobic component of gum base comprising melted methyl-, glyceryl- or pentaerythritol esters of polymerised resins. The taste was prolonged to 20 minutes. Eur. Patent 0217109 describes microencapsulation of flavours to prolong their release from chewing gum from a few minutes to about half an hour.
13. US Patent 4087557

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Sustained Release of sweeteners and flavours (Contd.)
Broderick et al.14 combined embedding of a sweetener in water insoluble beads of a copolymer of divinylbenzene and styrene followed with coating of the beads with a water soluble agent such as HPMC, or water insoluble agents such as shellac and wax for prolonged release of sweetener. If both the chewing gum base and the porous polymeric beads contain sweeteners, the polymeric beads will act as isolated reservoirs to release sweetener in a delayed fashion after sweetener has already been released from the chewing gum base itself.
14. US Patent 5139787
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Applications
Dental caries – Chewing gum formulations can control the release rate of active substances providing a prolonged local effect. Fluoride containing gums are useful in preventing dental caries in children and in adults with xerostomia (dry mouth). Chlorhexidine chewing gum can be used to treat gingivitis, oral infections, inhibition of plaque growth. Systemic therapy – a) Pain- Treatment of muscular aches, headache b) Smoking cessation – Chewing gum formulations containing nicotine, lobeline have been clinically tested as aids to smoking cessation.
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Applications
Obesity – Chromium, caffeine and guaran are proved to be efficient in treating obesity. Chromium reduces craving for food due to an improved blood-glucose balance. Caffeine and guaran stimulate lipolysis and have a thermogenic effect and reduce feeling of hunger. Other indications – Xerostomia, Motion sickness, Cold and Cough, Anxiety

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Non Medicated Chewing Gum
The chewing of non medicated chewing gum stimulates salivation thereby increasing the pH and hence reducing demineralization in early caries. It is claimed that sugar free chewing gum containing xylitol has caries reducing properties.

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Safety Aspect
Some disadvantages of chewing gum are: Broken teeth ( while chewing hard chewing gum) Painful Jaw Muscle (due to over chewing) Diarrhoea (in case of extensive use of sorbitol containing chewing gums due to its osmotic laxative effect) Lesser chances of overdosing even if swallowed as chewing action is necessary for drug release. Medicated chewing gums, like all other medicaments, be kept out of reach of children. People who are allergic to flavours and sweeteners should check the agents included in the chewing gum formulations.
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Marketed Products of Medicated Chewing gums
Brand Name Nicorette®, Nicotinell ® V6 Travvell Fluomin Aspergum Asagan ®
® ®

Active Ingredient Nicotine Xylitol

Indication Smoking cessation

Prevention of formation of dental caries Dimenhydrinate Motion sickness Cariostatic Pain relief
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Sodium fluoride and Aspirin

Conclusion
Chewing gum is a viable alternative to traditional dosage forms for drugs intended to cure or relieve diseases in the oral cavity. It can be used for systemic drug delivery where a rapid onset of action is needed like motion sickness, nausea, headache (provided the drug is easily absorbed through oral mucosa). If drug release is poor due to its inherent physicochemical properties the release promoting agent may be used or addition of a pH modifier for acidic or basic drugs or inclusion of surfactant could be the first approach.

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Conclusion
If there is need to reduce the rate of release of drug from chewing gum, coating or embedding methods could be considered; for ionic drugs complexation with an ion exchange resin might be an approach worth considering. The taste of the drug is an important factor to consider during formulation. Although much knowhow has been obtained in the pharmaceutical industry of how to mask the taste of a drug with a very bitter taste it is an insurmountable obstacle to overcome in the formulation of a medicated chewing gum.
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Conclusion
In the future, we may see the concept of chewing gum as a drug delivery system used more often in preference to other oral mucosal drug delivery systems for the local and systemic delivery of certain drugs. The reason is that chewing gum has controlled release properties, prolonged release properties, is convenient and easy to administer, is acceptable to the patient and can be taken discretely without water.

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