INTRODUCTION:

Taste, smell, texture and after taste are important factors in the development of dosage forms¹. These are important factor in product preference. Good flavor and texture are found to significantly affect sell of the product. Undesirable taste is one of the important formulation problems encountered with most of the drugs². The methods most commonly involved for achieving taste masking include various chemical and physical methods that prevent the drug substance from interaction with taste buds³. The simplest method involves use of flavor enhancers. Where these methods fail more complex methodologies are adopted. Various techniques have been identified for taste masking which include polymer coating, inclusion complex formation with cyclodextrin, use of ion exchange resins, solubility limiting methods, liposome, multiple emulsions, use of anesthetic agents, etc^4,5. The present review attempts to give a brief account of different technologies of taste masking with respect to dosage form along with novel methods of evaluation of taste masking effect⁶.

Organoleptic characteristics mainly appearance, odor and taste of pharmaceutical products carries great importance⁷. Masking of the unpleasant taste of a drug improves the compliance of the patient and product value Pharmaceutical companies are investing much time, money and resources in developing palatable, pleasant tasting products because good tasting products not only enhance the patient compliance but also provide a competitive advantage when a therapeutic category is crowded with similar products (e.g. anti-infective) and provide brand recognition to combat private-label competition⁸. Taste masking is defined as a perceived reduction of an undesirable taste that would otherwise exist⁹. 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 saltiness¹⁰. Thus in the present days, taste masking of bitter agents in the pharmaceutical industry has become commercially motivated activity for huge success of the product

Recent years have seen a tremendous progress in the techniques of masking the unacceptable taste of orally administered pharmaceuticals. Filling in capsules, adding flavors and sweeteners, use of lipoproteins for inhibiting bitterness, numbing of taste buds, coating of drug with inert agents, microencapsulation, multiple emulsion, viscosity modifiers, vesicles and liposomes, prodrug formation, salt formation, formation of inclusion and molecular complexes, solid dispersion system and application of ion exchange resins are various approaches available to the formulator¹¹. The present review deals in detail about all those approaches used for masking the taste of the bitter drugs.

Physiology of taste-

Sweet, sour, bitter and salty. That's it; pal, unless you want to count umami, the weird, nearly-indescribable sensation associated with monosodium glutamate. Every time you stick something in your maw, one or a combination of those four primary tastes alerts you to vital information about that mouthful of matter. If it's sweet, maybe it's got the nutrients your body needs to keep running for another few hours. If it's salty, perhaps you can replace some of those vital minerals you just excreted through sweat or urine. If it's sour, there's a chance it's not ripe and will give you a bad bellyache. If it's bitter, watch out -- it could be poison and your next swallow will be your last Open your mouth and say, "Aaahh!" There's your tongue, that pink, flexible muscle marinating in saliva.

You might call the little knobs dotting the surface of your tongue taste buds, but you'd be wrong. Those are papillae, and there are four kinds of them: fungi form and filiform on the front half, foliate and vallate on the back. The actual taste buds, described variously as resembling tiny navel oranges or onions, cluster together in packs of two to 250 within the papillae. The buds in turn consist of up to 100 cells, either receptor or basal. When something tasty enters the mouth, its chemicals are dissolved by the saliva, and the free-floating molecules enter the taste bud through a pore in its centre. If the molecule binds to the tip of a receptor cell, it will excite that cell into issuing a series of chemical and electrical signals. It used to be thought that these electrical signals would then be fired directly into the brain, but the process turns out to be more complicated than that.

For example, sweet and some bitter taste stimuli activate a chemical messenger known as gustducin, member of the old and venerable G-family of proteins and cousin to transducin, the protein in the eye which helps to translate light into vision. In ways not completely understood, the activation of gustducin initiates an electrochemical dialogue among the receptor cells, which then transmit their messages to the basal cells at the bottom of the bud. The basal cells can also "talk" back to the receptor cells and among themselves. Once everybody has their stories straight, the data are relayed to the brain, to the gustatory cortex to be specific"Geez, that's sweet," Salty and sour molecules don't seem to need to mess around with the receptor tips, permeating the taste cells directly through special channels in their walls. For example, the channels allow electrically charged sodium ions in and potassium ions out. As the interior of the cell grows progressively more positively charged, it sets up a small electric current that triggers more intercellular messages and, once again, word is passed to the brain that something salty, perhaps a pretzel, is about to plummet down the esophagus.

Smell, of course, doesn't simply warn against spoiled food. It also increases your enjoyment of practically everything you eat. Much of what we commonly refer to as "flavor" is actually a combination of smell and taste, with taste most often assuming the secondary position. The olfactory receptor cells are actually neurons, or nerve cells, outfitted at their knobby ends with six to twelve hair-like cilia. The cilia dangle into the thin layer of mucus that coats the membrane and snag passing particles for smell analysis. Each receptor cell is connected by a single primary olfactory neuron to one of the brain's two olfactory bulbs. The primary olfactory neurons pass through holes in the cribriform plate, a penny-thin bone at the front of the cranial cavity upon which the olfactory bulb rests. The primary neurons come together in structures known as glomeruli and there meet secondary neurons. Viral infections and head trauma are among the leading culprits. Viruses can kill off olfactory cells, which usually grow back but sometimes don't. A blow to the back of the head can send the brain careening at high speed into the front of the skull, severing the delicate connections between olfactory neurons¹². Exposure to toxic chemicals can rob you of your sense of smell, and benzene, chlorine, mercury and various insecticides have all been implicated in various cases. Loss of smell can also be one of the early symptoms of Alzheimer's and Parkinson's diseases, leading some researchers to theorize that the agents that cause those maladies enter the central nervous system through the olfactory nerve, damaging it in the process

Fig.no.1: Mechanism of Taste receptor³

Advantages of taste masking :-

Several oral pharmaceuticals and bulking agents have unpleasant, bitter-tasting components. The desire of improved palatability in these products has prompted the development of numerous formulations with improved performance and acceptability. This paper reviews different methods are available to mask undesirable taste of the drugs, with the applications. Popular approaches in the development of taste masking are based on coating, solid dispersion system and ion exchange resin¹³.

The advantages of taste masking are,

1) Involve least number of equipments and processing steps.

2) Require minimum number of excipients for an optimum formulation.

3) No adverse effect on drug bioavailability.

4) Require excipients that are economical and easily available.

5) Least manufacturing cost.

6) Can be carried out at room temperature.

7) Require excipients that have high margin of safety.

Methods of Taste Masking:-

Various methods are available to mask undesirable taste of the drugs. Some of these are as given below.

1. Coating of drug particles with inert agents

Coating is an extremely useful technique for number of applications in the pharmaceutical field. By coordinating the right type of coating material it is possible to completely mask the taste of a bitter drug, while at the same time, not adversely affecting the intended drug release profile. Any nontoxic polymer that is insoluble at pH 7.4 and soluble at acidic pH, would be an acceptable alternative for taste masking.

Taste masking of ibuprofen has been successfully achieved by using the air suspension coating technique to form microcapsules, which comprises a pharmaceutical core of a crystalline ibuprofen and methacrylic acid copolymer coating that provides chewable taste masked characteristics¹⁴.

Various inert coating agents like starch; povidone, gelatin, methylcellulose, ethyl cellulose etc. are used for coating drug particles. One of the most efficient method of drug particle coating is the fluidized bed processor. In this approach powder’s as fine as 50µm, are fluidized in expansion chamber by means of heated, high velocity air and the drug particles are coated with a coating solution introduced usually from the top as spray through nozzle. The coated granules are dried with warm air.

2. Taste masking by formation of inclusion complexes

In inclusion complex formation, the drug molecule fits into the cavity of a complexing agent i.e., the host molecule forming a stable complex. The complexing agent is capable of masking the bitter taste of the 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. Vander Waals forces are mainly involved in inclusion complexes.

Fig no.2: Beta Cyclodextrin ¹⁵

Beta-cyclodextrin is most widely used complexing agent for inclusion type complexes. It is sweet, nontoxic, cyclic oligosaccharide obtained from starch. Strong bitter taste of carbapentane citrate syrup was reduced to approximately 50% by preparing a 1:1 complex with cyclodextrin. The suppression of bitter taste by cyclodextrin was in increasing order of alpha, gamma, and beta cyclodextrin¹⁵.

3 Molecular complexes of drug with other chemicals:

The solubility and adsorption of drug can be modified by formation of molecular complexes. Consequently lowering drug solubility through molecular complex formation can decrease the intensity of bitterness of drug.Higuchi and Pitmanreported that caffeine forms complexes with organic acids that are less soluble than xanthenes and as such can be used to decrease the bitter taste of caffeine.

4. Microencapsulation:

Microencapsulation as a process has been defined by Bokanas a means of applying relatively thin coating to small particles of solid, droplets of liquid and dispersion. This process can be used for masking of bitter tasting drugs microencapsulating drug particles with various coating agents. Coating agents employed includes gelatin, povidone, HPMC, ethyl cellulose, Bees wax, carnauba wax, acrylics and shellac. Bitter tasting drugs can first be encapsulated to produce free flowing microcapsules, which can then be blended with other excipients and compressed into tablets. Microencapsulation can be accomplished by variety of methods including air suspension, coacervation, phase separation, spray drying and congealing, pan coating, solvent evaporation and multiorifice centrifugation techniques.

Fig no.3 Microencapsulation¹

Fig no.4; Techniques of Microencapsulation¹³

5. Using Liposome’s

Another way of masking the unpleasant taste of therapeutic agent is to entrap them into liposome. For example, incorporating into a liposomal formulation prepared with egg phosphatidyl choline masked the bitter taste of chloroquine phosphate in HEPES (N-2-hydroxyetylpiperzine-N’- 2- ethane sulfonic acid) buffer at pH 7.2.

fig no.5: Process of formation of liposomes2

6. Prodrugs:

A prodrug is a chemically modified inert drug precursor, which upon biotransformation liberates the pharmacologically active parent drug.

Table no.1 :Some of Prodrugs with improved Taste of parent drug⁸

Sr. no.	Parent drug	Prodrug with improved taste
1	Chloramphenicol	Palmitate ester
2	Clindamycin	Palmitate ester
3	Triamcinolone	Diacetate ester

6. Mass extrusion method (Dispersion coating):

This technology involves softening the active blend using the solvent mixture of water-soluble 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 taste

7. Ion Exchange Resin:

Another popular approach in the development of taste masking is based on ion exchange resin. Ion exchange resins are solid and suitably insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium. The resulting ion exchange is reversible and stiochiometric with the displacement of one ionic species by another.Synthetic ion exchange resins have been used in pharmacy and medicine for taste masking or controlled release of drug as early as 1950.

Being high molecular weight water insoluble polymers, the resins are not absorbed by the body and are therefore inert. The long-term safety of ion exchange resins, even while ingesting large doses as in the use of cholestyramine to reduce cholesterolis established unique advantage of ion exchange resins is due to the fixed positively or negatively charged functional groups attached to water insoluble polymer backbone. The adsorption of bitter drugs onto synthetic ion exchange resins to achieve taste coverage has been well documented. Ion exchange resins like Amberlite CG 50 were used for taste masking of pseudoephedrine in the chewable Rondec decongestant tablet.

Antibacterial belonging to quinolone category like ciprofloxacin was loaded on cation exchanger and administered to animals. The taste was improved as animal accepted the material more readily.¹⁸ Binding to a cation exchange resin like Amberlite IRP-69 masked the taste of peripheral vasodilator buflomid. Manek S.P.et al. evaluated resins like Indion CRP 244 and CRP 254 as taste masking agents. Some bitter drugs whose taste has been masked by using ion exchange resin are listed in the table

Table no.2: Bitter Drugs masked by ion exchange resin⁸

Drug	Ion exchange resin
Norfloxacin	Indion 204 (weak cation exchange resin)
Ciprofloxacin	Indion 234 (weak cation exchange resin)
Roxithromycin	Indion 204 (weak cation exchange resin)
Chloroquine phosphate	Indion 234 (weak cation exchange resin)

Ion exchange resins (IER) have received considerable attention from pharmaceutical scientists because of their versatile properties as drug delivery vehicles. In past few years, IER have been extensively studied in the development of Novel drug delivery system and other biomedical applications. Several ion exchange resin products for oral and peroral administration have been developed for immediate release and sustained release purposes. Research over last few years has revealed that IER are equally suitable for drug delivery technologies, including controlled release, transdermal, nasal, topical, and taste masking¹⁶.

Taste Masking of Different Dosage Forms:-

The drug i.e. the active pharmaceutical ingredient is finally formulated in a suitable dosage form such as tablet, powder, liquid, etc.

I) Tablets:

Most of the tablets can be effectively masked for their taste by applying inert polymer coatings that prevent the interaction of the drug substance with the taste buds. Nevertheless, attempts have been made time and again by several workers to investigate and explore the use of newer materials in bad taste abatement and good taste enhancement

II) Granules / Powders:

Granules for reconstituting as liquids (e.g. sachets, sprinkle capsules and powders) hold a high share of pediatric and geriatric market. A large number of patents on the topic highlight the significance of the same. Thus taste masking of granules becomes an important priority in product development and varied technologies and methodologies exist for the same as illustrated below. Hayward et al. have reported a granular composition for taste masking comprising of drug core of a NSAID and methacrylate ester copolymers as coating agents for taste masking¹⁷. The method comprises of coating the drug cores with separate layers of aqueous dispersions of the copolymers. Granules of the invention could be used in the preparation of chewable tablets, which had good palatability and bioavailability.

III) Liquids:

They present a major challenge in taste masking because the majority of pediatric preparations are syrups and suspensions although, the aforementioned methodologies have- also had been used for improving liquid taste and few patents in this area are worth mentioning. Nakona et al. masked the bitter taste of vitamin B1 derivatives such as dicethimine by formulating with menthol and or polyoxyethylene, polyoxypropylene for formulating oral liquids. Osugi et al. in their invention subjected oral liquids containing Diclofenac and its salts to heat treatment in the presence of glycine, glycerrhizinic acid or salt thereof to mask the bitter taste and to prevent the irritation of the throat upon oral administration¹⁸.

Technology used for taste masking¹³:

1. Bitter Blocker Technology:

Bitter blockers work by interfering with taste transduction, the process by which taste message travel from the mouth to the brain. Transduction begins with the interaction of a tastant (e.g., medicine or food) with taste receptor cells in the taste buds. The tastant binds with G-protein coupled receptors (GPCRs) in the cells, triggering the release of a G-protein called gustducin. The process of taste sensation begins when gustducin activates the effector enzymes phosphodiesterase 1A (PDE) or phospholipase C beta-2 (PLC). The effector enzyme then changes the intracellular level of second messenger such as cyclic adenosine monophosphate (cAMP), inositol 1, 4, 5-triphosphate (IP3), and diacylglycerol (DAG). The second messengers activate ion channels, including calcium channels inside the cell, and sodium, potassium, and calcium channels on extracellular membrane. This ionization depolarizes the cell, causing the release of neurotransmitter send a nerve impulse to the brain that carries the signal of bitter taste.

Fig.no.6 :Bitter Blocker¹³

Fig.no.7 Bitter taste transduction¹³

2. Use of flavour enhancers:

The materials for taste masking purpose have often been classified depending upon the basic taste that is masked Flavoring and perfuming agents can be obtained from either natural or synthetic sources. Natural products include fruit juices, aromatic oils such as peppermint and lemon oils, herbs, spices and distilled fractions of these. They are available as concentrated extracts, alcoholic or aqueous solutions, syrups or spirit. Apart from these conventional materials many compositions have been found to show effective taste masking abilities with improved flavor such as alkaline earth oxide, alkaline earth hydroxide or an alkaline hydroxide.Another composition includes phosphorylated amino acid such as phosphotyrosine, phosphoserine, and phosphothreonine and mixtures. Anethole effectively masked bitter taste as well as the aftertaste of zinc, which is use in treating the common cold. Clove oil and calcium carbonate, which has been found to be particularly useful to mask the unpalatable active in formulations which are intended to be chewed or dissolve in mouth prior to ingestion in solution.

3. Applying polymer coatings:

Coating of drugs using a suitable polymer offer an excellent method of concealing the drug from the taste buds. The coated composition may be incorporated into much number of pharmaceutical formulations, including chewable tablet, effervescent tablets, powder, and liquid dispersion. Objective being prevention of drug release in the mouth while ensuring rapid release in GIT.

4. Complexation with ion exchange resins:

The adsorption of bitter drugs onto synthetic ion exchange resins to achieve taste coverage has been well documented. Borodkin et al. prepared high potency adsorbates of methapyrilene, dextromethorphan, ephedrine, pseudoephedrine by column procedures using a polymethacrylic acid ion exchange resin. Taste evaluation of the adsorbates showed a significant reduction in the bitterness of the drugs. Coating the adsorbate particles with 4:1 ethyl cellulose - HPMC mixture reduced the bitterness further. Taste coverage was maintained after incorporation of the coated adsorbate into chewable tablets. Strong acid cation resins (sulfonated stynedivinylbenzene copolymer product) can be used for masking the taste of basic drugs. Polystyrene matrix cation exchange resins have been used to mask the bitter taste of chlorpheniramine maleate, ephedrine hydrochloride, and diphenhydramine hydrochloride. Extreme bitterness of quinolones has been achieved by ion exchange resin such as methacrylic acid polymer cross linked with divinylbenzene.Cyclodextrin is the most widely used complexing agent for inclusion complex formation which is capable of masking the bitter taste of the drug either by decreasing its solubility on digestion or decreasing the amount of drug particles exposed to taste buds there by reducing its perception of bitter taste. Bitter taste of ibuprofen and gymnema sylvestre has been effectively masked by cyclodextrin.

5. Other techniques:

These include solubility-limiting methods, incorporation of drugs in vesicles and liposome, and chemical modification. The solubility limiting method can be applied to a number of drugs whose taste profiles are dependent on aqueous solubility.

Chemical modification such as derivatization or lipophillic counter ion selection may be an effective method for reducing aqueous solubility and taste Erythromycin monohydrate, a bitter tasting drug with a solubility of 2 mg/ml is chemically converted into erythromycin ethyl succinate, the aqueous solubility is reduced to the < 50 mcg/ml. This form is tasteless and can be administered as a chewable tablet. Incorporation of drugs into vesicles or liposomes is although an ideal technique, yet a challenge to formulate without altering the regulatory status of the product (in vitro dissolution kinetics, physical or chemical stability or bioavailability).

Anesthetizing agent like sodium phenolate, which numb the taste buds sufficiently within 4-5 seconds is helpful in inhibiting the perception of bitter taste of the formulation. Substances like lipids, carbohydrate, lecithin, gelatin and polyamines has been effectively used for taste masking of drugs.

Another novel technique employing multiple emulsions has also been reported. By dissolving drug in the inner aqueous phase of w/o/w emulsion under condition of good shelf stability, the formulation is designed to release drug through oil phase in the presence of gastric fluid. In one of the method drugs with bitter taste are combined with nonionic surfactants to form composites by hydrophobic interactions resulting in taste masking.

CONCLUSION:

Taste of drugs requires skillful application which does not affect the bioavailability of drug. With application of these techniques and proper evaluation of taste masking effect one can improve product preference to a large extent. Moreover, the development of taste masking methodology requires great technical skill, and the need for massive experimentation. Several approaches namely sensory, barrier, chemical and complication have been tried to mask the unpleasant taste of formulation. Palatability is recognized as being a critical factor in patient compliance, particularly for children in whom the acceptability of medicament and hence its ease of administration can be greatly affected by taste. In the present review approaches used for the taste masking of the pharmaceuticals are discussed in detail

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Received on 15.10.2011 Modified on 28.10.2011

Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 152-157