**2. Taste masking**

There are numerous pharmaceutical and over the counter (OTC) preparations that contain active ingredients, which are bitter in taste. With respect to OTC preparations, such as cough and cold syrups, the bitterness of the preparation leads to lack of patient compliance. Among

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

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

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

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

There are numerous pharmaceutical and over the counter (OTC) preparations that contain active ingredients, which are bitter in taste. With respect to OTC preparations, such as cough and cold syrups, the bitterness of the preparation leads to lack of patient compliance. Among

foods, while bitterness serves as a warning sign of poisons [6].

known how PLC activates TRPM5 or whether DAG is involved [8-18].

**2. Taste masking**

taste bud.

400 Application of Nanotechnology in Drug Delivery

**C**

[22] and (12) amoxicillin (15) (Figure 2), a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other β-lactam antibiotics. Amoxicillin is one of the most common antibiotics prescribed for children. The drug became available in 1972 [22].

**3. Challenges and criteria for pursuing masking bitter taste approaches**

with drugs known to have a good safety profile [27-29].

**4. Bitter taste masking approaches (techniques)**

The most significant challenges that facing developers when pursuing masking bitter taste drugs approaches are: (i) Safety, tolerability and efficacy of the compound which are based on non-clinical testing, and physicochemical properties such as solubility, permeability and stability, (ii) lack of robust and reliable techniques for early taste screening of compounds with limited toxicity data, (iii) structure–taste relationships of pharmaceutically active molecules is limited, (iv) The perception of taste of pharmaceuticals has been shown to be different between adults and children and it might differ between healthy and patient children [4] and (v) ethical concerns to perform taste studies in healthy children unless the study is a 'swill and spit' one

Prodrugs for Masking the Bitter Taste of Drugs

http://dx.doi.org/10.5772/58404

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A variety of taste masking approaches has been used to address the patient compliance problem. With strongly bad tasting medications even a little exposure is sufficient to perceive the bad taste. Conventional taste masking methods such as the use of sweeten‐ ers, amino acids and flavoring agents alone are often inadequate in masking the taste of highly bitter drugs. Drugs such as macrolide antibiotics, non-steroidal anti-inflammatory such as ibuprofen (**16**) (Figure 2), quinine (**17**) (Figure 2), celecoxib (**18**) (Figure 3), etoricox‐ ib (**19**) (Figure 3), levofloxacin (**20**) (Figure 3)and penicillins have a pronounced bitter taste [30]. Masking the taste of water soluble bitter drugs, especially those given in high doses, is difficult to achieve by using sweeteners alone. As a consequence, several approaches have been investigated and have resulted in the development of more efficient techniques for masking the bitter taste of active ingredients. All of the developed techniques are based on the physical modification of the formulation containing the bitter tastant. Among the approaches used to mask bitter taste of pharmaceuticals are: (1) taste masking using flavors, sweeteners, and amino acids. This technique is the foremost and the simplest approach for taste masking, especially in the case of pediatric formulations, chewable tablets, and liquid formulations. However, it is not an ideal to be used for highly bitter and highly water soluble drugs. An example for such approach is the use of monosodium glycyrrhizinate together with flavors to mask the bitter taste of guaiphenesin (**14**) (an expectorant drug) Taste masked lamivudine (antiretroviral drug) was prepared by using lemon, orange and coffee flavors [3,31]; (2) taste masking with lipophilic vehicles such as: i) Lipids; acetamino‐ phen granules are sprayed with molten stearyl stearate, mixed with suitable tablet excipients, and incorporated into a taste masked, chewable tablet formulation and (ii) lecithin and Lecithin-like substances; formulations with lecithin or lecithin-like substances in large quantities are believed to efficiently mask bitter taste of pharmaceuticals [3]. An example of a drug formulation containing lecithin-like substance is the one composed of magnesium aluminum silicate with soybean lecithin and talampicillin HCl (**21**) (antibiotic drug) (Figure 3); (3) coating is one of the most efficient and commonly used taste mask‐

**Figure 1.** Chemical structures for **1-9.**
