Review Article Nilima Thombre et al. / Journal of Pharmacy Research 2011,4(3),848-851 ISSN: 0974-6943 Available online through http://jprsolutions.info A review on medicated gum as a novel system

Nilima Thombre*, Karishma Patel Mumbai Education Trust’s Institute of Pharmacy, Bhujbal Knowledge City, Adgaon, Nashik-422003, Maharashtra, India Received on: 05-10-2010; Revised on: 14-12-2010; Accepted on:09-02-2011

ABSTRACT Medicated Chewing gum, in addition to its role also has a proven value as a drug delivery vehicle for pharmaceutical and nutraceutical ingredients. It can be taken discreetly without water and allows for local and systemic delivery. It was employed for treatment of diseases of the oral cavity and throat for caries prevention. The present drug delivery technology can release drugs through oral mucosa directly into the systemic circulation. In addition, drug that is not absorbed by the oral cavity membranes can be dissolved in the saliva before swallowing, thus leading to a more rapid onset of action. Medicated Chewing Gum is applied as pharmaceutical vehicle or a drug delivery system to administer active principles that can improve health and nutrition. The present article reviews Medicated Chewing Gum Drug Delivery System concepts including its merits and demerits, material, methods of preparation, some important formulation aspect, method for evaluation.

Key words: Medicated chewing gum,Novel Drug Delivery System

INTRODUCTION Pharmacologically Active Agents or Drugs are formulated into variety of dosage forms like Merits of Medicated Chewing Gum: (1,4) Tablets, Capsules, Injectables, , Ointments etc considering Physicochemical proper- Chewing gums do not require water in order to swallow. Hence it can be taken anywhere. Thus, ties, Pharmacokinetic & Pharmacodynamic parameters and Biopharmaceutical aspects of it can be advantageous for patients having difficulty in swallowing. It is highly accepted by Drugs; however, recently in addition to its confectionary role, Chewing Gum also has proven children. Moreover, Medicated Gums have recently found wide applications in treatment of dry great value as a delivery vehicle for pharmaceutical and nutraceutical ingredients. It can be taken mouth, prevention of candidiasis and caries. discreetly without water and the drug is allowed for local and systemic delivery. It can be employed for treatment of diseases of the oral cavity and throat e.g. for caries prevention, or it It is excellent in cases of acute or short term medications. E.g.: can release drugs that can be absorbed through oral mucosa directly into the systemic Cessation Products. The bioavailability of the drugs can be increased through medicated gums circulation. In addition, drug that is not absorbed by the oral cavity membranes can be as they help in avoiding First Pass Metabolism and fast onset due to rapid release of active dissolved in the saliva before swallowing, thus leading to a more rapid onset of action. The ingredients in buccal cavity and subsequent absorption in systemic circulation. Medicated Chewing Gums (MCG) can also be utilized for site specific activity in case of oral cancer1. It is important to note that gum does not reach the . Hesnce G.I.T. suffers less from the effects of excipients. Stomach does not suffer from direct contact with high concentrations of Many therapeutic agents are absorbed in the oral cavity. For the drugs having significant buccal active principles, thus reducing the risk of intolerance of gastric mucosa. Fraction of product absorption, dosage forms such as Lozenges, Chewable tablets and Chewing Gum permits reaching the stomach is conveyed by saliva delivered continuously and regularly. Thus, more rapid therapeutic action compared to per-oral dosage forms. Chewable tablets and duration of action is increased. Aspirin, Dimenhydrinate and Caffeine shows faster absorption chewing gum have been very well received by the parents for use in children with full dentition. through Medicated Chewing Gum than tablets5. Children in particular may consider chewing gum as a more preferred method of drug admin- istration compared with oral and tablets. The use of Medicated Chewing Gum is Demerits Of Medicated Chewing Gum: feasible in local treatment of diseases of oral cavity as well as treatment of systemic conditions2. There is always a risk of over dosage with Medicated Chewing Gum compared to chewable The first patent for the production of chewing gum was filed in 1869 and was issued to Mr. W. tablets or lozenges as Medicated Chewing Gums can be consumed in a considerable number F. Semple in Ohio under U. S. Patent No. 98,304. A Medicated Chewing Gum containing and within much shorter period of time6. Acetyl Salicylic Acid was commercially introduced in 19283. In 1991, Chewing Gum was approved as a term for pharmaceutical dosage form by the commission of European Council. present in Medicated Chewing Gum formulation may cause flatulence, diarrhoea. The majority of chewing gum delivery systems today are manufactured using conventional Additives in gum like flavoring agent, Cinnamon can cause Ulcers in oral cavity and Licorice gum processes. The is softened or melted and placed in a kettle mixer where cause Hypertension. Chlorhexidine oro-mucosal application, which is used as to treat gingivi- sweeteners, , active ingredients and other excipients are added at a defined time. The tis, periodontitis, oral and pharyngeal infections is limited to short term use because of its gum is then sent to a series of rollers that form it into a thin, wide ribbon. During this process, unpleasant taste and staining properties to teeth and tongue. 7 a light coating of finely powdered or is added to keep the gum from sticking and to enhance the flavor. Finally, the gum is cut to the desired size and cooled at a Chewing gums have been shown to adhere to different degrees to enamel dentures and fillers8. carefully controlled temperature and humidity1. Prolong chewing on gum may result in pain in facial muscles and earache in children9.

Owing to new social and behavioral trends in the past modern age, such as the growing Materials10: consumer health awareness and increasing attention to safety products, chewing gum has been The characteristic component of all Chewing Gums is the gum base. Other component added known for a new image and potential. Chewing gum today is gaining consideration as a to Chewing Gums typically includes sweetening agents, flavoring agents and aromatics. In vehicle or a delivery system to administer active principles that can improve health and medicated Chewing Gum active drug is incorporated. nutrition. A gum base comprises of a complex mixture of elastomers, natural of synthetic , fats, Medicated Chewing Gum represents the newest system with potential uses in pharmaceuti- emulsifiers, , antioxidants, fillers and flavoring agents. cals, over the counter medicines and nutraceuticals. The drugs intended to act in oral cavity often have low water or saliva and chewing gum constitute a valuable delivery 1. Elastomers: They provide elasticity and cohesion to the chewing gum. Natural elas- system for such drugs4. tomer, Natural rubbers like or Natural gums such as Jelutong, Lechi Caspi, Perillo, and synthetic elastomers like polyisobutylene and butyl rubber are used. 2. Resins: They serve two functions; one, as mastication substance and other as binding *Corresponding author. agent between elastomers and fillers they contribute to the balance between the prop- Nilima Thombre erties of elasticity and plasticity. Glycerol esters from pine resins are examples of natu- Mumbai Education Trust’s Institute of Pharmacy, ral resins. Synthetic can be used. It reduces the tendency of the gum to adhere to the teeth (detackifier) and to be divided into pieces during chewing. Bhujbal Knowledge City, It has only a slight taste with good stability. Adgaon, Nashik-422003, Maharashtra, India 3. Emulsifiers and fats: These are used to soften the mixture and give the required chew-

Journal of Pharmacy Research Vol.4.Issue 3. March 2011 848-851 Nilima Thombre et al. / Journal of Pharmacy Research 2011,4(3),848-851 ing consistency and mouth feel. Emulsifiers promote the uptake of saliva into the the various coolants like nitrogen, slush use of solid carbon dioxide is chewing gum during mastication. Monoglycerides, diglycerides and partly hardened preferred as it can give temperatures as low as 78.50C. The solid carbon dioxide sublimes vegetable and animal fat are used. readily on warming the mixture and is not absorbed by the chewing gum composition. It does 4. : Natural and Synthetic plasticizers are used to regulate cohesiveness of product. Natural Plasticizers include Natural esters like Glycerol Esters or not interact adversely with the processing apparatus and does not leave behind any residue partially hydrogenated Rosin, Glycerol Esters of Polymerized Esters, Glycerol Esters which may be undesirable or potentially hazardous. The refrigerated composition is then of Partially dimerized Rosin & Pentaerythritol Esters of Rosin. Synthetic crushed or ground to obtain minute fragments of finely ground pieces of the composition. Plasticizers include Terpene Resins derived from a-pinene and/or d-limonene. Alternatively, the steps of cooling the chewing gum composition can be combined into a 5. Antioxidants: They may be added to protect the gum base and flavors from oxidation. single step. The grinding apparatus itself is cooled by keeping the grinding apparatus in Ascorbic acid, tocopherol, butylhdroxytoluene have been used. contact with a coolant or by placing the grinding apparatus in a cooling jacket of liquid 6. Fillers: They provide the right texture for the gum base. Talc, calcium carbonate can be nitrogen or other cold liquid. For more efficient cooling, the chewing gum composition can be used. 7. Colorants and Whiteners may include FD & C type dyes and lakes, fruit and veg- pre cooled prior to cooling to the refrigeration temperature. etable extracts, Titanium Dioxide. 8. Sweeteners: Sugar Components include Saccharides like Sucrose, Dextrose, Maltose, Sometimes a mixture of chewing gum composition, solid carbon dioxide and precipitated Dextrin, , Galactose, and Corn . Sugarless Components include sugar silica is ground in a mill grinder in a first grinding step. Additional solid carbon dioxide and alcohols such as Sorbitol, , , hydrogenated Starch hydrolysate. High silica are added to the ground composition, and the composition is further ground in a second intensity artificial sweeteners can also be included to provide longer lasting sweet- grinding step. This two step grinding process advantageously keeps the chewing gum ness and flavor e.g. Sucralose, Aspartame, salt of Acesulfame, composition at a very low temperature. The presence of solid carbon dioxide also serves to Alitame,Saccharin, Glycerrhizin, Dihydrochalcones. Aqueous Sweeteners can also enhance the efficiency of the grinding process. The same process can be made multiple by be used as softeners to blend the ingredients and retain moisture. These include Sor- bitol, hydrogenated Starch hydrolysates and Corn Syrups. Corn syrup keeps gum incorporating additional carbon dioxide and/or precipitated silica at each step. fresh and flexible. 9. Flavouring Agents: A variety of flavouring agents are used to improve flavour in Certain additives can be added to the chewing gum composition to facilitate cooling, grinding chewing gum includes essential oils, such as Citrus oil, fruit essences, oil, and to achieve desired properties of chewing gum. These include use of anti-caking agent and Spearmint oil, oil, Clove oil & Oil of . Artificial flavouring agents grinding agent. can also be used. 10. Active Pharmaceutical Drugs: In medicated chewing gum active pharmacological Once the coolant has been removed from the , the powder can be mixed with other agent may be present in core or coat or in both. The proportion of which may vary from 0.5-30% of final gum weight. A small, unionized, lipophilic and enzymatically stable ingredients such as binders, lubricants, coating agents, sweeteners, etc. all of which are active agent is likely to be absorbed more readily. A saliva soluble ingredient will be compatible with the components of the chewing gum base in a suitable blender such as sigma completely released within 10-15 minutes of chewing whereas lipid soluble ingredi- mill or a high shear mixer. ent will dissolve in the gum base and thereafter be slowly and completely absorbed. MCG consists of masticatory gum core that may be coated. The core is composed of an Alternatively a Fluidized Bed Reactor (FBR) can also be used. The use of FBR is advanta- aqueous insoluble gum base which can be mixed with Sweeteners and Flavors. The geous as it partially rebuilds the powder into granules, as well as coats the powder particles or coating can be applied as a film of , waxes, sweeteners, flavors and colour or granules with a coating agent thereby minimizing undesirable particle agglomeration. The a thick layer of sugar or . granules so obtained can be mixed with antiadherents like talc. The mixture can be blended in Table 1: Optimal Properties of Drug 11 a V type blender, screened & staged for compression. Compression can be carried out by any conventional process like punching. Physicochemical Properties of Drug High Salivary Solubility pH independent solubility Tasteless Cooling, Grinding and Tabletting Method thus overcomes the limitations of Conventional Non-toxic to oro-mucosa and salivary ducts technique. However, it requires equipment other than conventional tabletting equipment thus Non-carcinogenic Patient Related Factors Should not cause making it expensive process as compared to Conventional process. Similar to the Conven- Should not cause oro-mucosa and teeth staining tional process even this process requires careful monitoring of humidity during the tabletting Should not affect salivary flow rate process.

Note: Requirements of drug candidate for Chewing Gum. (1,13) 1) The drug should not have any type of disagreeable taste, this can affect patient compliance. 3. Direct Compression Chewing Gum : 2) The particle size of the drug should be kept below approximately 100 microns to avoid unpleas- SPI pharma has developed a compatible gum system known as Pharmagum. Pharmagum is ant gritty feeling during chewing2. a mixture of and of sugar with gum base. Pharmagum® S consists primarily of gum Methods of Preparation: base and sorbitol. Pharmagum® M contains gum base, Mannitol and Isomalt. These are free Different methods can be Employed for the manufacturing of Chewing Gum; however, these flowing , which are directly compressible. The gum is manufactured under CGMP can be broadly classified into three main classes namely: conditions and complies with chemicals. Direct compression chewing gum can be 1.Conventional/ traditional Method (Melting). directly compressed on a traditional tabletting machine, thus enabling rapid and low cost 2.Cooling, grinding and tabletting Method. development of a gum delivery system. 3.Direct Compression Method Some Important Formulation Aspect: 1.Conventional/ traditional Method 2: 1.Hard gum retards the drug release, which can be increased by increasing the amount of softeners 6 Components of gum base are softened or melted and placed in a kettle mixer to which and emulsifiers in gum base . sweeteners, syrups, active ingredients and other excipients are added at a definite time. The 2. Drugs with poor water solubility can be complexed with Cyclodextrin or can be subjected to (6,14) gum is then sent through a series of rollers that forms into a thin, wide ribbon. During this solubilisation technique to increase its aqueous solubility . process, a light coating of finely powdered sugar or sugar substitutes is added to keep the gum 3.A solid system of lipophilic active ingredients bound to the cation exchange resin permits a away from sticking and to enhance the flavor. In a carefully controlled room, the gum is cooled sustained drug delivery system. for upto 48 hours. This allows the gum to set properly. Finally the gum is cut to the desired 4. Microencapsulation or agglomeration is the method to modify and control the release of active (15,16) size and cooled at a carefully controlled temperature and humidity. However, the conventional ingredient . method has number of limitations like elevated temperature used in melting, restricts the use of this method for thermo labile drugs. Controlling of accuracy and uniformity of drug dose Factors Affecting Release Of Active Ingredient: becomes difficult due to melting and mixing of highly viscous gum mass makes. Such a 1. Contact Time: chewing gum composition is difficult to form into chewing gum tablets because of their The local or systemic effect is dependent on time of contact of Medicated Chewing Gum in oral cavity. In clinical trial chewing time of 30 minutes was considered close to ordinary use. The moisture content (2-8%). If attempted to grind and such a composition would jam the 17 grinding machine, stick to blades, screens adhere to punches and would be difficult to average chewing rate is about 60 chews every minute . compress. Technology not so easily adaptable to incorporate the stringent manufacturing conditions required for production of pharmaceutical products. 2. Physicochemical properties of active ingredient: Physicochemical properties of active ingredient plays very important role in release of drug 2.Cooling,Grinding and Tabletting Method(2,12): from Medicated Chewing Gum. The saliva soluble ingredients will be immediately released This method has been developed with an attempt to lower the moisture content and alleviate within few minutes whereas lipid soluble drugs are released first into the gum base and then the problems faced in conventional method. The Chewing Gum composition (base) is cooled released slowly. Release of water soluble drug (aqueous solubility greater than 1:10) is, in to a temperature at which the composition is sufficiently brittle and would remain brittle during general, about 75% or more during 5 min. of chewing and 90% or more during 15 min. of the subsequent grinding step without adhesion to the grinding apparatus. The temperature chewing at rate of 60 chews per minute. Drugs with aqueous solubility between 1:10 and 1:300 required for cooling is determined in part by the composition of the Chewing Gum and is 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 easily determined empirically by observing the properties of the cooled chewing gum compo- 18 sition. Generally the temperature of the refrigerated mixture is around -15oC or lower. Amongst only be expected to be small (less than 5%) even if the gum is chewed for 30 min .

Journal of Pharmacy Research Vol.4.Issue 3. March 2011 848-851 Nilima Thombre et al. / Journal of Pharmacy Research 2011,4(3),848-851 3. Inter individual variability: There are two apparatus for studying release from chewing gum – The chewing frequency and chewing intensity which affect the drug release from Medicated 1) MASTICATOR M 36 Chewing Gum may vary from person to person. In-vitro study prescribed by European 2) Instrument for In-vitro dissolution of medicated chewing gums 6-cell chewing apparatus. Pharmacopoeia suggest 60 cycles per minute chewing rate for proper release of active ingredi- ent3. 1) “MASTICATOR M 36” 13: Christrup and Moller’s experiences prompted them to design a new chewing gum machine. 4. Formulation factor: This machine consists of a temperature-controlled reservoir for dissolution medium and two Composition and amount of gum base affect rate of release of active ingredient. If lipophilic pistons. During one chewing cycle, the piston one on each side move towards each other, fraction of gum is increased, the release rate is decreased.19 The influence of gum base mass on pressing the chewing gum between them and then make a twisting movement before returning drug release has been investigated using salicylamide as model drug. When salicylamide was to starting point. At specified time intervals, a sample is removed from the reservoir and incorporated into a chewing gum, which contained a relatively large percentage of gum bases, quantity of drug released is determined. The cycle rate (chewing rate) is usually set at 60 per the release after 30 min. of chewing was significantly lower (25.6%) compared to a gum in minute, and 20 mL of dissolution media equilibrated to 37° are typical volumes and tempera- which less gum base was present (52%) 17. tures of dissolution media.

Product Performance Tests For Medicated Chewing Gums: 2) Instrument for In-vitro dissolution of medicated chewing gums 6-cell chewing In European Pharmacopoeia medicated chewing gums have been separately categorized under apparatus13: solid dosage forms. However, medicated chewing gums also could be defined both as solid and The apparatus designed by Christrup and Moller has been developed further which allows six semisolid preparations based on the art of manufacturing, i.e., using conventional melting pieces of chewing gum to be evaluated at the same time. In addition to the two horizontal procedures2 or direct compression of tailored gum-base powder13. Table 1 shows the product pistons, the chewing chambers are supplied with vertical piston working staggered to the quality tests associated with the chewing gum preparations described in European Pharmaco- horizontal piston. This ensures that the gum is always positioned in the right place during the poeia in general and specifically with nicotine polacrilex resins and gums in USP. mastication process. One cycle of the piston consist of one upward and one downward stroke,

1 with cycle frequencies of 7.5-30 every minute. Simultaneously, the plunger consistently Table 2: Product Quality Tests for Medicated Chewing Gums rotates during the experiments at 10-40 rpm and a cycle frequency of 30 cycles per minute were found to give release rates similar to those observed in vivo. Dosage Nature Nature Patient Safety Test Product Quality Form Activation Requirement Tests The apparatus of Christrup and Moller has been used in many studies with different formula- Medicated gums Solid/semi-solid Yes Yes Assay Identification tions of chewing gums containing drug of wide range of aqueous . In general the Uniformity of dosage results have shown a high correlation between in vitro and in vivo release data. Moreover, the units, content, and mass fact that six pieces of chewing gum can be examined at the same time is advantageous as it In addition to the product quality tests, additional testing specific to the product may be provides results at a faster rate and can be expected to be more reproducible than the results performed to ensure the final quality of the finished product. This may include, for example, obtained with the original apparatus developed by Christrup and Moller. The 6-cell chewing texture analysis, product feel and consistency, evaluation of flavors and sweeteners, tests for apparatus is the world’s only commercially available instrument for in-vitro dissolution of coatings, impurities, water content, degradation products, residual solvents, etc. Product chewing gums. performance tests also are included at times by some manufacturers as a quality control tool and are employed during the early phase of product development. USP does not contain a Therapeutic uses of medicated chewing gum: compendial apparatus for performance testing of medicated chewing gums. Thus in many cases The use of sugar free gum to counteract dental caries by stimulation of saliva secretion has led to a more widespread use and acceptance of gums. It has been proved that chewing non- product performance data were generated by apparatus developed by the drug product manufac- 23 turers and are not contained in the public monograph. medicated chewing gums increases plaque pH, stimulates saliva flow and decrease decay . Medicated Chewing Gums containing Chlorhexidine for treatment of gingivitis and plaque has been available. The use of Medicated Chewing Gum in the treatment of oral infections has also European Pharmacopoeia has adopted an apparatus to determine the release rate from chewing 24 gums formulations. The basic principle is a simple masticatory movement employed to been reported . The active ingredient is released from the Medicated Chewing Gum and simulate the chewing action on a piece of gum placed in a small chewing chamber containing sufficient concentration is achieved in the oral cavity to prevent or treat local conditions of oral a known volume of buffer at a given temperature. The drug release rate is influenced cavity. by the chewing rate and angle, which provides the necessary shear force to expose new gum surfaces and is a requisite for further drug release20. Chewing Gum is also useful delivery system for agents intended for systemic delivery. Drug that is released from gum within oral cavity can be absorbed via buccal mucosa. The Medicated Apparatus I: Chewing Gum Apparatus, Compendial - European Pharmacopoeia21 Chewing Gums can also be used as an alternative tool to buccal and sublingual tablets which The chewing apparatus comprises a chewing chamber, two horizontal pistons, and a third are intended to act systemically because active ingredient is released more uniformly and cover vertical piston (tongue). The vertical piston operates alternatively with the two horizontal greater area of absorption in oral cavity. Oral diseases are prevented or cured with Medicated pistons and makes sure the gum stays in the right place between chews. If necessary, it is Chewing Gum. Medicated Chewing Gums for systemic effect in conditions like vitamin C deficiency24, pain & fever25, alertness 26 , motion sikness27 , smoking cessation28, as well as for feasible to construct the machine so that at the end of the chew the horizontal pistons rotate 29 18 30 around their own axes in opposite directions to each other to obtain maximum chewing. local effect in the conditions like plaque acid neutralization , fresh breath , disinfection , anti-caries 31, antiplaque32, antifungal33 , antibacterial9 are available. Apparatus II: Alternative Chewing Gum Apparatus, Noncompendial – Wennergren22 The chewing procedure consists of reciprocations of the lower surface in combination with a REFERENCES: 1. Morjaria Y, Irwin WJ, Barnett PX, Chan RS and Conway BR: In Vitro Release of Nicotine from shearing (twisting) movement of the upper surface that provides mastication of the chewing Chewing Gum Formulations. 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Journal of Pharmacy Research Vol.4.Issue 3. March 2011 848-851