Poonam et al - Galaxy of Pharmaceutical Innovations
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Poonam et al - Galaxy of Pharmaceutical Innovations
Poonam et al Review article Galaxy of Pharmaceutical Innovations (Journal for Pharmaceutical Innovators) Home page: www.gopionline.com Volume 1, Issue 1, February-March 2015 Taste masking technology for pharmaceutical dosage forms: a review Poonam Mandawat Dept. of Pharmaceutics, Shrinathji institute of Pharmacy, Nathdwara, Rajasthan-313301 * E-mail: [email protected] ARTICLE INFO ABSTRACT Article History Received 17 March 2015 Revised 23 March 2015 Accepted 27 March 2015 Keywords Taste Oral Mask Approaches Pharmaceutical, nutraceutical, nutritional, and other active materials typically have an objectionable taste which creates challenges for some forms of oral delivery. If it is confined to a tablet or capsule that is swallowed whole, the material can pass the taste buds without significant detection. When the material is formulated as a chewable tablet, a fast-dissolve lozenge or film, solution or suspension, objectionable taste is often the primary cause of patient non-compliance with a dosing requirement. The present review article provides different approaches for masking the taste of bitter taste drugs. INTRODUCTION Taste is one of the most important parameters governing patient compliance. Undesirable taste is one of several important formulation problems that are encountered with certain drugs. Oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients. Several oral pharmaceuticals, numerous food and beverage products, and bulking agents have unpleasant, bitter-tasting components. So, any pharmaceutical formulation with a pleasing taste would definitely be preferred over a competitor's product and would translate into better compliance and therapeutic value for the patient and more business and profits for the company. 22 www.gopionline.com The desire of improved palatability in these products has prompted the development of numerous formulations with improved performance and acceptability1 Sense of taste Taste, or gustatory perception, is one of our basic senses. It tells us from early childhood what is edible and what is not, what is good for our body and what can be potentially dangerous. Taking into account how important the sense of taste is for us, it is surprising how little we know about the underlying neurological mechanisms that produce the sensation of taste2. Different Types of taste Scientists describe seven basic tastes: bitter, salty, sour, astringent, sweet, pungent (eg chili), and umami. There are however five basic tastes that the tongue is sensitive to: salt, GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article sweet, bitter, sour, and umami, the taste of MSG. Umami is a Japanese word meaning "savory" or "meaty" and thus applies to the sensation of savoriness -- specifically, to the detection of glutamates, which are especially common in meats, cheese and other proteinheavy foods. The action of umami receptors explains why foods treated with monosodium glutamate often taste fuller or just better3. PHYSIOLOGY OF TASTE The sense of taste is mediated by taste receptor cells which are bundled in clusters called taste buds. Taste receptor cells sample oral concentrations of a large number of small molecules and report a sensation of taste to centers in the brainstem. Taste buds are composed of groups of between 50 and 150 columnar taste receptor cells bundled together like a cluster of bananas. The taste receptor cells within a bud are arranged such that their tips form a small taste pore, and through this pore extend microvilli from the taste cells. The microvilli of the taste cells bear taste receptors4. The sense of taste affords an animal the ability to evaluate what it eats and drinks. At the most basic level, this evaluation is to promote ingestion of nutritious substances and prevent consumption of potential poisons or toxins. There is no doubt that animals, including humans, develop taste preferences. That is, they will choose certain types of food in preference to others. Interestingly, taste preference often changes in conjunction with body needs. Taste Receptor Cells, Taste Buds and Taste Nerves TASTE MASKING TECHNOLOGY Taste masking is defined as a perceived reduction of an undesirable taste that would otherwise exist. The ideal solution to reduce or inhibit bitterness is the discovery of a universal inhibitor of all bitter tasting substances that does not affect the other taste modalities such as sweetness or saltiness. Two comprehensive reviews to control bitter taste have already been presented along with thoughts on the discovery of a universal bitterness inhibitor5,6 An appreciable amount of success has been achieved in the development of bitterless, tasteless, and taste‐masked formulations in recent years. Various techniques available for masking bitter taste of drugs include taste masking with ingredients such as flavors, sweeteners, and amino acids; taste masking by polymer coating; taste masking by conventional granulation; taste masking with ion‐exchange resins; taste masking by spray congealing with lipids; taste masking by formation of inclusion complexes with cyclodextrins; taste masking by the freeze‐drying process; taste masking by 23 www.gopionline.com making multiple emulsions; and taste masking with gelatin, gelatinized starch, liposomes, lecithins or lecithin‐like substances, surfactants, salts, or polymeric membranes7. Selection of Taste Masking Technique Appropriate selection of a taste masking technique is a must for developing a palatable and economical formulation. For instance, a drug that is extremely bitter cannot be taste masked with sweeteners or flavorants alone, and intermediary techniques like coating or matrix entrapment should be used. An ionic drug can be taste masked with ion exchange resins. A lipophilic drug can be taste masked by entrapping it into a lipoidal matrix. Although variations are possible, in general simple techniques are more economical as compared to intermediary ones. Ideal Taste Masking Process Involve least number of equipments and processing steps. Require minimum number of excipients for an optimum formulation. GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article No adverse effect on drug bioavailability. Require excipients that are economical and easily available. Least manufacturing cost. Can be carried out at room temperature. Require excipients that have high margin of safety Rapid and easy to prepare8 Factors That Are Taken Into Consideration during the TasteMasking Formulation Process Extent of the Bitter Taste of the API With aggressively bad tasting medicaments even a little exposure is sufficient to perceive the bad taste. For example, sweeteners could not achieve taste masking of oral formulation of ibuprofen due to its dominating taste. Coating is more efficient technology for aggressively bitter drugs even though coating imperfections, if present, reduce the efficiency of the technique9. Similarly, microencapsulation of potent bitter active agents such as azithromycin is insufficient to provide taste masking of liquid oral suspensions10.Conventional taste masking techniques such as the use of sweeteners, amino acids and flavoring agents alone are often inadequate in masking the taste of highly bitter drugs such as quinine, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and clarithromycin11. Required dose load Dose of a drug may dictate whether a particular formulation strategy would be suitable to achieve taste masking. In paediatric formulations, the dose is small enough so as to allow the usage of flavouring agents to mask the taste of the medicine. For example, low dose palatable paediatric aspirin oral formulation was developed by adding sweeteners, but the same approach failed to address the problem of drugs like acetaminophen because of its high dose. In 24 www.gopionline.com such cases, coating is preferred to achieve taste masking along with sweeteners to attain an acceptable final dosage form size 12 . Drug particulate distribution shape and size Particle characteristics of the drug would affect the taste masking process efficiency. Core materials with irregular shapes and small particle size lead to poor taste masking efficiency and varying dissolution of coated particles. Fines, abrasion and variable coating thickness can lead to situations wherein the taste mask coating is compromised. Multilayer coating using inner spacing layer to sequester the drug from taste masking layer helps to reduce or eliminate such coating imperfections. Taste masked granules of gatifloxacin and dextromethorphan were formulated by multilayer coating consisting of inner spacing layer followed by outer taste masking layer.13 Drug solubility Physicochemical properties of the drug play an important role in the selection of taste masking technology. For example, ondansetron has a relatively lower water solubility at higher pH, based on which a rapidly disintegrating taste masked composition of ondansetron was formulated by adding an alkalizing agent(sodium bicarbonate) to reduce the water solubility and the consequent taste perception14 Ionic characteristics of the drug Ionic characteristics of drugs govern the selection of ion exchange resin polymers and the suitability of the drug candidate for this technology. For example, anionic polymers (e.g. alginic acid) are good candidates for cationic drugs like donepezil hydrochloride, and the cationic polymers are choice of excipients for anionic drugs like sildenafil15,16 Required dosage form It is estimated that 50% of the population have problem of swallowing tablets, especially the paediatric and geriatric population. Chewable tablets and liquid oral dosage forms have been used to address these problems. However, it is difficult to formulate some drugs in these GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article dosage forms due to their poor palatability. For formulations which are swallowed unchewed: capsules, coated tablets and slowly disintegrating hard tablets have been used as . preferred taste masking technologies. Chewable tablets and liquid oral formulations are preferable in case of large dose drugs for an ease of intake17,18 DIFFERENT TASTE TECHNOLOGY flavors for masking the taste of ammonium chloride and other saline drugs has also been established. The various imitation flavor concentrates used are grape, maple, raspberry, and wild cherry, etc. These have been compared to some of the official flavored syrups and recognized as good masking agents for saline drugs24. Flavors Natural Flavors Juices – Raspberry Extracts – Liquorices Spirits - Lemon & Orange Syrups – Blackcurrant Tinctures –Ginger Aromatic waters - Anise & Cinnamon Aromatic Oils – Peppermint & Lemon. Synthetic Flavors Alcoholic solutions Aqueous solutions Powders Sweetners Complement flavors associated with sweetness Soothing effect on the membranes of the throat Natural Sweetener Sucrose, glucose, fructose Sorbitol, mannitol, glycerol Honey, liquorice Artificial Sweetener Saccharin, Saccharin sodium Aspartame Nutritive: Sucrose, Fructose and Glucos Polyols: Mannitol, Sorbitol, Xylitol, Erythritol, Maltitol. Non-Nutritive: Aspartame, Sucralose, Neotame and Saccharin24 MASKING Taste Masking with Sweeteners, and Amino Acids Flavors, This technique is the foremost and the simplest approach for taste masking, especially in the case of pediatric formulations, chewable tablets, and liquid formulations. But this approach is not very successful for highly bitter and highly water soluble drugs. Artificial sweeteners and flavors are generally being used along with other taste‐masking techniques to improve the efficiency of these techniques. Numerous pharmaceuticals such as dentifrices and mouthwashes applied to the oral cavity elicit unpleasant taste perceptions19. The unpleasant taste of certain formulations like mouthwashes and cough drops containing medicinal and bitter tasting substances such as eucalyptus oil can be masked by adding fenchone, borneol, or isoborneol. These taste masking agents significantly suppress the perception of unpleasant organoleptic sensations of the volatile oil20. The cooling effect of the taste masking agents also aids in reducing the bitterness. Sweetening compositions of di‐D‐fructofuranose 1,2′: 2,3′‐di‐anhydride are also useful for dentifrices, mouthwashes, and foods. Menthol reduces the bitter taste, and low‐calorie formulations show beneficial anticaries effects21. Nonbitter dentifrices are prepared by sweetening benzethonium chloride with stevia‐based sweetener extract and glycerin. It exhibits 100% bactericidal activity against E. coli22. Anethole and menthofuran in various dentifrices are not only used to mask the bitterness but also to improve the low temperature stability of the formulation23. The use of some imitation 25 www.gopionline.com GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article Taste masking by microencapsulation It is important to understand that only soluble portion of the drug can generate the sensation of taste. And it is possible, or even likely, that coating the active drug with a properly selected polymer film can reduce its solubility in saliva in thus taste could be masked.Coating the drug particles created a physical barrier between the drug and the taste buds and this taste of active could be masked. Microencapsulation is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with film or polymeric material25. Taste masking complexation by inclusion In inclusion complex formation,the drug molecule fits into the cavity of a complexin agent ,i.e. the host molecule,forming a stable complex. The complexing agent is capable of masking the bitter taste of drug by either decreasing its oral solubility on ingestion or decreasing the amount of drug particles exposed to taste buds, thereby reducing the perception of bitter taste. This method is most suitable only for low dose drugs. Vander Walls forces are mainly involved in inclusion complexes. β-cyclodextrin is the most widely used complexing agent for inclusion type complexes. It is a sweet, non-toxic, cyclic oligosaccharide obtained from starch. The strong bitter taste of carbetapentane citrate syrup was reduced to approximately 50% by preparing a 1:1 complex with cyclodextrin1. Palatable ibuprofen solutions are prepared by forming a 1:11 to 1:15 inclusion complex with Ibuprofen and hydroxy propyl Bcyclodextrin, respectively. Taste Masking by Hydrophilic Vehicles Coating with This is the simplest and most feasible option to achieve taste masking. The coating acts as a physical barrier to the drug particles, thereby minimizing interaction between the drug and taste buds. Coating of chewable tablets 26 www.gopionline.com provides excellent taste masking while still providing acceptable bioavailability. A specialized technique, i.e., micro emulsion technology, has been used for taste masking of powders, chewable tablets, and liquid suspensions. Taste Masking By Granulation Granulation is a less expensive, rapid operation and an easily scalable taste masking technology. This step can be exploited as a mean for taste masking of slightly bitter tasting drug. Granulation lowers the effective surface area of the bitter substance that come in contact with the tongue upon oral intake. Liquid and low melting point waxes such as glycerol palmitostearate, glyceryl behenate and hydrogenated castor oil are commonly used ingredients during the granulation to achieve taste masking.26 Taste masking by ion exchange resins Based on Complexation of drugs with ion exchange resins. Ion exchange resins are water insoluble, cross linked high molecular weight polyelectrolytes containing salt forming groups in repeating position on the polymer chain which exchange their mobile ion of equal charge with the drug molecule. As taste perception of bitter drugs is experienced in the mouth at taste buds, complexed drugs resinate does not release drug in mouth due of scarcity of exchangeable ions (at pH 6.7) in the saliva and when complex comes in contact with GIT fluids (at acidic pH),complex is broken down quickly and drug is release. Resins being polyelectrolyte have extensive binding sites leading to very high drug loading ability Ion exchange resins have received considerable attention because of their versatile properties as drug delivery vehicles, chemically inert and free from local and systematic side effects possess long-term safety even while ingesting large doses and also compatible with all conventional solid, semisolid and liquid dosage forms. GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article Use of Amino Acids And Protein Hydrates By combining amino acids or their salts with bitter drugs, it is possible to substantially reduce the bitterness. Some of the preferred amino acids include sarcosine, alanine, taurine, glutamic acid, and glycine. The taste of ampicillin improved markedly by preparing its granules with glycine and mixing them with additional quantity of glycine, sweeteners, flavors and finally compressing them into tablets27. Taste masking by bitterness inhibitors The development of a specific universal inhibitor for bitter taste has been widely required in the fields of taste physiology and pharmaceutical sciences, but no such inhibitors has been available.One difficulty in discovering of universal inhibitor for bitter taste is that substances that inhibits bitterness of one compound will not influence the bitterness of a second because many different classes of compound impart bitterness. Sodium salts such as sodium chloride, sodium acetate, sodium gluconate have been shown to be potent inhibitors of some bitter compounds. The mechanism is not known, however, research shows that sodium act at peripheral taste level rather than a cognitive effect. Bitter substances are commonly hydrophobic in nature hence lipoprotein (PA?LG) composed of phophatidic acid and β lactoglobulin can mask the target sites for bitter substances on the taste receptor membrane without affecting responses to salts, acids, sugars or sweet amino acids.28. Viscosity modification Enhancement of viscosity in liquid formulations by thickening agents such as natural gums or carbohydrates can mask the unpleasant taste of drug by formulating a covering layer on the tongue and act as barrier between drug particles and taste buds, thus lowering the diffusion of drug from saliva into the taste buds13. For viscosity enhancement in 27 www.gopionline.com liquid formulations, polyethylene glycols and carboxy methylcellulose are induced which not only increases the stability of liquid formulation but surprisingly, provides taste masking of unpleasant tasting medicines. For examples, in cough syrups, terbutaline given in doses of 4mg/5ml can be effectively administered by increasing the viscosity of the formulation29. Taste masking by prodrug approach Chemical modification, including prodrug design is an effective method for reducing solubility, and thereby improving taste. A prodrug is chemically modified inert drug precursor which upon biotransformation liberates the pharmaceutically active parent compound. Bitterness of a molecule may be due to the efficiency of the taste receptor substrate adsorption reaction, which is related to the molecular geometry of the substrate. If alteration of the parent molecule occurs by derivative formation, the geometry is altered, affecting the adsorption constant. Thus the magnitude of a bitter taste response or taste receptor-substrate adsorption constant may be modified by changing the molecular configuration of the parent molecule. The extremely bitter antibiotics have been the focus of much work in reversible drug modification30. Taste masking by gelation Water insoluble gelation on the surface of tablet containing bitter drug can be used for taste masking. Sodium alginate has the ability to cause water insoluble gelation in presence of bivalent metal ions. Tablet of amiprolose hydrochloride have been taste masked by applying a undercoat of sodium alginate and overcoat of calcium gluconate. In presence of saliva, sodium alginate reacts with bivalent calcium and form water insoluble gel and thus taste masking achieved31. Development of liposome Another way of masking the unpleasant taste of therapeutic agent is to entrap them into GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article liposome. For example, incorporating into a liposomal formulation prepared with egg phosphatidyl choline masked the bitter taste of chloroquine phosphate in HEPES (N-2hydroxyetylpiperzine-N‟- 2- ethane sulfonic acid) buffer at pH 7.232. solubility through molecular complex formation can decrease the intensity of bitterness of drug Higuchi and Pitman, reported that caffeine forms complexes with organic acids that are less soluble than xanthan and as such can be used to decrease the bitter taste of caffeine35 Taste masking by adsorption Adsorbates are commonly used in taste masking technologies. Adsorbate of bitter tasting drug can be considered as the less saliva soluble versions of these drugs. Adsorption involves preparing a solution of the drug and mixing it with an insoluble powder that will adsorb the drug, removing the solvent, drying the resultant powder, and then using these dried adsorbates in the preparation of the final dosage form. Many substrates like veegum, bentonite, silica gel and silicates can be used for the reparation of adsorbate of bitter drugs.The bitter taste of ranitidine is masked by forming an adsorbate with a synthetic cation exchange resin33. Use of multiple emulsion A novel technique of taste masking of drug employing multiple emulsions. The w/o/w or o/w/o type multiple emulsion are vesicular systems in which active ingredients can be entrapped in internal phase. The entrapped substances can be transferred from internal phase to external phase through the membrane phase. This phase controls the release of drug from system. These system could be used for controlled-release delivery of pharmaceuticals. If the system is stable enough for a reasonable shelf life, the formulation could also mask the taste of drug. Both w/o/w or o/w/o multiple emulsion of chloroquine phosphate have been prepared and reported to be partially effective in masking the bitter taste of drug34. Molecular complexes of drug with other chemicals The solubility and adsorption of drug can be modified by formation of molecular complexes. Consequently lowering drug 28 www.gopionline.com Mass extrusion method This technology involves softening the active blend using the solvent mixture of watersoluble polyethylene glycol, using methanol and expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablets.The dried cylinder can also be used to coat granules of bitter tasting drugs and thereby masking their bitter taste36. Use of salts or derivatives In this approach, an attempt is made to modify the chemical composition of the drug substance itself, so as to the taste buds. Aspirin tablets can be rendered tasteless by making magnesium salt of aspirin. Dchlorpheniramine maleate is taste-masked salt of chlorpheniramine. The alkyloxy alkyl Carbonates of Clarithromycin have remarkably viated bitterness and improved bioavailability when administered[65]. Sodium salts such as sodium chloride, sodium acetate, sodium gluconate have been shown to be potent inhibitors of some bitter compound. The mechanism is not known, however, research shows that sodium act at peripheral taste level rather than a cognitive effect 37 Use of desensitizing agents Desensitizing agents like phenols, sodium phenolates desensitize the taste buds by interfering with taste transduction the process by which taste message from the mouth to the brain and thus mask the taste of drug.38 Wet spherical agglomeration (WSA) Technique (CMT) and Continuous Multipurpose Technology. A novel GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article microencapsulation process combined with the wet spherical agglomeration (WSA) technique was used to mask the bitter taste of enoxacin. The microcapsules prepared were bioequivalent to the commercial Enoxacin 100 mg tablets in beagle dogs. The CMT method was developed for the continuous granulation and coating of pharmacologically active substances. It was concluded that this method could be successfully applied for taste masking of bitter drugs39 pH modifiers Many natural and synthetic polymers, resins and waxes alone or in combination have been employed for taste masking. The enteric polymers like eudragit L are used for taste masking but the pH of saliva is near 5.8 and these polymers solubilize at pH beyond 5.5 so there is a possibility of drug being partially leached. Therefore there is a need for the development of taste masking polymer such that the bitter taste is completely masked by the polymer at the pH of saliva in mouth and in the reconstitution medium as in case of the liquid orals and further which is able to protect the drug in a biologically active form, from the moisture in the dosage form and releasing the drug rapidly in the stomach without affecting its absorption and bioavailability.40. Miscellaneous taste masking approaches by effervescent agents Effervescent agents have been shown to be useful and advantageous for oral administration of drugs and have been employed for use as taste masking agents for dosage forms that are not dissolved in water prior to administration. A chewing gum composition of bitter medicament was formulated to supply the medicament to oral cavity for local application or for buccal absorption. It comprise a chewing base, an CONCLUSION Taste masking of bitter drugs has significantly improved the quality of treatment provided to 29 www.gopionline.com orally administrable medicament, a taste masking generator of carbon dioxide, and optionally a taste bud desensitizing composition (e.g., oral anesthetic such as benzocaine) and other non active material such as sweeteners, flavoring components, and fillers.Recently, effervescent tablets of fentanyl and prochlorperazine were developed to supply these drugs to the oral cavity for buccal, sublingual, and gingival absorption. The formulation contains the drug in combination with effervescent agent to promote their absorption in the oral cavity and to mask their bitter taste. An additional pH adjusting substance was also included in fentanyl formulation for further promotion for absorption 41. Rheological modification Increasing the viscosity with rheological modifier such as gums or carbohydrates can lower the diffusion of bitter substances from the saliva to the taste buds. Acetaminophen suspension can be formulated with xanthan gum (0.1?0.2%) and microcrystalline cellulose (0.6?1%) to reduce bitter taste. The antidepressant drug mirtazapine is formulated as an aqueous suspension using methonine (stabilizer) and maltitol (thickening agent). Maltitol is stable in the acidic pH range of 2 to 3 and besides masking the unpleasant taste of the drug, it also inhibit its undesirable local anesthetic effect 42 Continuous multipurpose melt (cmt) technology The cmt method was developed for the continuous granulation and coating of pharmacologically active substances. It was concluded. That this method could be succesfully applied for taste masking of bitter drugs43 suffering patients, especially children. The word „medicine‟ for a child is synonymous with bad taste. Oral pharmaceuticals have been GOPI, Vol 1(1) feb-mar 2015 Poonam et al Review article continually adapted for making their “bitter taste better”, especially to the pediatric and the geriatric consumers. There are so many effective techniques and methodologies that are constantly being researched and developed in the pharmaceutical field in response to the need of taste masking. Applicability of all REFERENCES 1. Pubfacts, Taste masking technologies in oral pharmaceuticals: recent developments and approaches. Available online at, http://www.pubfacts.com/detail/15244 079/Taste-masking-technologies-inoral-pharmaceuticals:-recentdevelopments-and-approaches. 2. Brainbloger, how the sense of taste works, available online at http://brainblogger.com/2014/12/09/ho w-the-sense-of-taste-works/ 3. 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