**1. Introduction**

The palatability of the active ingredient of a drug is a significant obstacle in developing a patient friendly dosage form. Organoleptic properties, such as taste, are an important factor when selecting a certain drug from the generic products available in the market that have the same active ingredient. It is a key issue for doctors and pharmacists administering the drugs and particularly for the pediatric and geriatric populations. Nowadays, pharmaceutical companies are recognizing the importance of taste masking and a significant number of techniques have been developed for concealing the objectionable taste [1].

The word "medicine" for a child is considered a bad thing to administer because of its aversive taste. Medicines dissolve in saliva and bind to taste receptors on the tongue giving a bitter, sweet, salty, sour, or umami sensation. Sweet and sour taste receptors are concentrated on the tip and lateral borders of the tongue respectively. Bitter taste is sensed by the receptors on the posterior part of the tongue and umami taste receptors are located all over the tongue. A short period after birth, infants reject bitter tastes and prefer sweet and umami tastes[1]. Children have larger number of taste buds than adults which are responsible for sensitivity toward taste. These taste buds regenerate every two weeks. Taste becomes altered as a function of the aging process, which explains why most children find certain flavors to be too strong when adults do not. The American Academy of Pediatrics estimates that compliance in children is as low as 53%, indicating that children frequently fail to take medications properly. Noncompliance can lead to: (1)persistent symptoms, (2) need for additional doctor visits or even hospitaliza‐ tions, (3) worsening of condition, (4) need for additional medications, (5) increased healthcare costs and (6) development of drug-resistant organisms in cases of infectious diseases [2].

In mammals, taste buds are groups of 30-100 individual elongated "neuroepithelial" cells which are often embedded in special structure in the surrounding epithelium known as papillae. Just below the taste bud apex, taste cells are joined by tight junctional complexes that prevent gaps

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between cells. Food molecules cannot therefore squeeze between taste cells and get into the taste bud.

examples that are commonly used drugs with bitter taste: (1) pseudoephedrine (1) (Figure 1),a sympathomimetic drug of the phenethylamine (2) (Figure 1) and amphetamine (3) (Figure 1) chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent [19], (2) dextromethorphan (4) (Figure 1), an antitussive (cough suppressant) drug. It is one of the active ingredients in many over-the-counter cold and cough medicines. Dextromethorphan has also found other uses in medicine, ranging from pain relief to psychological applications. It is sold in syrup, tablet, spray, and lozenge forms. In its pure form, dextromethorphan occurs as a white powder [20], (3) dyphylline (5) (figure1) also known as dipprophyllinea xanthine derivative withbronchodilatorandvasodilator effects. It is used in the treatment of respiratory disorders like asthma, cardiac, and bronchitis. It acts as an adenosine receptor antagonist and phosphodiesterase inhibitor [21].(4) phenylephrine (6) (Figure 1), is a selective α1-adrenergic receptor agonist used primarily as a decongestant, as an agent to dilate the pupil, and to increase blood pressure [22]. Phenylephrine is marketed as a substitute for the decongestant pseudoephedrine, (5) chlorhexidine (7) (Figure 1), a chemical antiseptic. It is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria. It has both bactericidal and bacteriostatic mechanisms of action, the mechanism of action being membrane disruption, not ATPase inactivation as previously thought [23]. It is also useful against fungi and enveloped viruses, though this has not been extensively investigated, (6) atorvastatin (8) (Figure 1), a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body [22], (7) loperamide (9) (Figure 1),a piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically [24].(8) terfenadine (10) (Figure 2), was an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis) and marketed under various brand names. According to its manufacturer, terfenadine had been used by over 100 million patients worldwide as of 1990 [25]. It was superseded byfexofenadine (11) (Figure 2) in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation) [22], (9) predniso‐ lone (12) (Figure 2), is a synthetic glucocorticoid, a derivative of cortisol, which is used to treat a variety of inflammatory and auto-immune conditions. It is the active metabolite of the drug prednisoneand is used especially in patients with hepatic failure, as these individuals are unable to metabolize prednisone into prednisolone [22], (10) salbutamol (13) (Figure 2), or albuterol (USAN) is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It is marketed as Ventolin among other brand names. Salbutamol was the first selective β2-receptor agonist to be marketed – in 1968. It was first sold by Allen & Hanburys under the brand name Ventolin. The drug was an instant success, and has been used for the treatment of asthma ever since [26]. (11) guaifenisen (14) (Figure 2), or guaiphenesin (former BAN), also glyceryl guaiacolate, is an expectorant drug sold over the counter and usually taken orally to assist the bringing up (expectoration) of phlegm from the airways in acute respiratory tract infections

Prodrugs for Masking the Bitter Taste of Drugs

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Taste papillae located on the tongue appear as little red dots, or raised bumps, particularly at the front of the tongue called "fungi form" papillae. There are three other kinds of papillae, foliate, circumvallates and the non-gustatory fili form. In mammals taste buds are located throughout the oral cavity, in the pharynx, the laryngeal epiglottis and at the entrance of the esophagus. Taste perception fades with age; on average, people lose half their taste receptors by time they turn 20 [3].The sensation of taste can be categorized into five basic tastes: sweetness, sourness, saltiness, bitterness, and umami. Taste buds are able to differentiate among different tastes through detecting interaction with different molecules or ions. Sweet, umami, and bitter tastes are triggered by the binding of molecules to G protein-coupled receptors on the cell membranes of taste buds. Saltiness and sourness are perceived when alkali metal or hydrogen ions enter taste buds, respectively [4].As taste senses both harmful and beneficial things, all basic tastes are classified as either aversive or appetitive, depending upon the effect the things they sense have on our bodies [5].Sweetness helps to identify energy-rich foods, while bitterness serves as a warning sign of poisons [6].

For a long period, it was commonly accepted that there is a finite and small number of "basic tastes" of which all seemingly complex tastes are ultimately composed. As of the early twentieth century, physiologists and psychologists believed there were four basic tastes: sweetness, sourness, saltiness, bitterness. At that time umami was not proposed as a fifth taste but now a large number of authorities recognize it as the fifth taste [7]. In Asian countries within the sphere of mainly Chinese and Indian cultural influence, pungency (piquancy or hotness) had traditionally been considered a sixth basic taste. Today, the consensus is that sweet,amino acid (umami), and bitter taste converge one common transduction channel, the transient receptor potential channel TRPM5, *via* phospholipase C (PLC). TRPM5 is a newly discovered TRP related to other channels in sensory signaling systems. It has been shown that PLC, a major signaling effect or of G-protein coupled receptors (GPCRs), and TRPM5 are co expressed with T1Rs and T2Rs and are vital for sweet, amino acid, and bitter taste transduction. Activation of T1R or T2R receptors by their respective taste molecules would stimulate G proteins, and in turn PLC (PLC-ß2). The activation of PLC generates two intracellular mes‐ sengers-IP3 and di-acyl glycerol (DAG)-from the hydrolysis of phosphatidylinositol-4,5 bisphosphate (PIP2)and opens the TRPM5 channel, resulting in the generation of a depolarizing receptor potential. Other additional pathways may modulate sweet, amino acid, or bitter taste reception but would not, themselves, trigger a taste response. It is not at present known how PLC activates TRPM5 or whether DAG is involved [8-18].
