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

[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

**Phenylethylamine (2)**

**NH2**

**N**

**O**

**N H N H N**

**H3C**

**O**

**<sup>N</sup> <sup>N</sup>**

**<sup>H</sup> NH NH**

**N**

**Lopramide (9)**

**OH <sup>N</sup>**

**Chlorhexidine (7)**

**O**

**CH3**

**Dyphyline (5)**

**Amphetamine (3)**

**OH**

**N**

**N H N H N**

**NH NH**

**NH2**

**OH**

**Cl**

**Cl**

children. The drug became available in 1972 [22].

**OH**

402 Application of Nanotechnology in Drug Delivery

**Pseudoephedrine (1)**

**N**

**Dextromethorphan (4)**

**Phenylephrine (6)**

**Atorvastatin (8)**

**HN O**

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

**OH**

**N**

**<sup>N</sup> HO <sup>H</sup>**

**H**

**H3C**

**H3**

**HN CH3**

**OCH3**

**H**

**F**

**OH OH O**

**Cl**

**OH**

**C**

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‐

ing techniques. It is more efficient technology for aggressively bitter drugs even though coating imperfections, if present, reduce the efficiency of the technique. Coating of tablets, pellets or any other kind of particles with a film-forming polymer is a successful ap‐ proach to provide a physical barrier, concealing unpleasant odors and bitter taste. Addition‐ ally, it can prevent penetration of moisture into the formulation. Coating materials can be selected from a wide range of hydrophobic and hydrophilic polymers such as polyvinylpyr‐ rolidone, polyvinyl alcohol and cellulose derivatives. The ideal polymer for taste-mask‐ ing, odor suppression and moisture protection should prevent dissolution of the dosage form in the mouth, but should be readily soluble in the stomach. Coating is classified based on the type of coating material, coating solvent system, and the number of coating layers. Taste masked famotidine (a drug for ulcer treatment) formulated by using a combination of water soluble polymers like polyvinylpyrrolidone and insoluble polymers like cellulose acetate is an example of such technique. Other various inert coating agents can be used to coat bitter drugs. These coating agents simply provide a physical barrier over the drug particles. Examples for such coating agents are starch, povidone, gelatin, methylcellulose, ethyl cellulose and etc. One of the most efficient Method of drug particle coating is the fluidized bed processor [4]. In this approach, powders as fine as 50 um are fluidized in an 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 a spray through a nozzle. Increasing the length of the coating cycle can increase coating thickness. Taste masking of Ibuprofen (**16**)(Figure 2) has been successfully achieved by this technique [4]; (4) microen‐ capsulation is a technique applicable to protect materials from oxidation, volatilizing as well as to mask their bitter tastes [6]. Microencapsulation processes are commonly based on the principle of solvent extraction or evaporation. Microencapsulation as a process has been defined by Bakan [6] as a means of applying relatively thin coating to small parti‐ cles of solid, droplets of liquid and dispersion. This process can be used for masking the bitter taste of drugs by 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 be first encapsulated to produce free flowing microcapsules, which are then blended with other excipients and com‐ pressed into tablets. Microencapsulation also increases the stability of the drug. It can be accomplished by a variety of methods, including air suspension, coacervation-phase separation, spray drying and congealing, pan coating, solvent evaporation and multiorifice centrifugation techniques; (5) taste suppressants and potentiators such as the Linguagen's bitter blockers (e.g. adenosine monophosphate) are used for masking bitter taste of various compounding by competing with the latter on binding to the G-protein coupled receptor sites (GPCR) [32]; (6) ion exchange resins are water insoluble, crosslinked polymers containing salt forming groups in repeating position on the polymer chain. Drug can be bound to the ion exchange resin by either repeated exposure of the resin to the drug in a chromatographic column or by prolonged contact of resin with the drug solution. The resins forms insoluble adsorbates or resinates through weak ionic bonding with oppositely charged drugs. The exchange of counter ions from resin is competitive.

Most of the bitter drugs have amine as a functional group, which is the cause of their obnoxious taste. If the functional groups are blocked by complex formation the bitterness of the drug reduces drastically. A drug-resin complex is made from the bitter drugs and ion-exchange resins. The nature of the drug-resin complex is such that the average pH of 6.7 and cation concentration of about 40 meq/ lit in saliva are not able to break the drugresin complex but it is weak enough to be broken down by the hydrochloric acid present in the stomach. Thus the drug: resin complex is absolutely tasteless and stable, with no after taste, but at the same time its bioavailability is not affected. Ion exchange resin like Amberlite was used to formulate taste masked fast dissolving orally consumable films of dextromethorphan (cough suppressant drug) [33,34]; (7) inclusion complexes in which the drug molecule fits into the cavity of a complexing agent forming a stable complex. The obtained complexing agent has the potential to mask the bitter taste of a drug by either decreasing its oral solubility on ingestion, or decreasing the amount of drug particles exposed to taste buds, thus reducing the perception of bitter taste. The inclusion com‐ plexes with cyclodextrin owe their existence to van der Waals forces between the host and guest. Cyclodextrin is the most widely used complexing agent for inclusion type com‐ plexes. It is a sweet, nontoxic, cyclic oligosaccharide derived from starch. Cyclodextrin forms inclusion complexes with organic molecules both in solid state and in solution [35]; (8) pH modifiers are capable of generating a specific pH microenvironment in aqueous media that has the ability to facilitate *in situ* precipitation of the bitter drug compound in saliva thus reducing the overall taste sensation for liquid dosage forms like suspension [36]; (9) adsorbates which are commonly used with other taste masking technologies to mask pharmaceuticals bitterness. The pharmaceutical may be adsorbed or/and entrapped in the matrix of the adsorbate porous, which may result in a delayed release of the bitter tastant during the passage through the oral cavity and hence achieving taste masking [37]; (10) chemicals; the solubility and absorption of drugs can be modified by the formation of molecular complexes. Lowering drug solubility through molecular complexation can decrease the intensity of bitterness. Higuchi and Pitman [38] reported that caffeine (**22**) (Figure 3) forms complexes with organic acids that are less soluble than xanthenes and as such can be used to decrease the bitter taste of caffeine; (11) solid dispersions; solid dispersion have been defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting (fusion) solvent or melting solvent method. Solid dispersion is also called as co precipitates for those preparation obtained by solvent method such as co precipitates of sulphathiazole (**23**) (Figure 3) and povidone. Solid dispersions using insoluble matrices or bland matrices may be used to mask the bitter taste of drugs. Also using them as absorbates on various carriers may increase the stability of certain drugs [39]; (12) multiple emulsions; a novel technique for taste masking of drugs employing multiple emulsions has been prepared by dissolving drug in the inner aque‐ ous phase of w/o/w emulsion under conditions of good shelf stability. The formulation is designed to release the drug through the oil phase in the presence of gastrointestinal fluid [40]; (13) using liposomes is another way of masking the unpleasant taste of therapeutic agent is to entrap them into liposome. For example, incorporating it into a liposomal

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405

Most of the bitter drugs have amine as a functional group, which is the cause of their obnoxious taste. If the functional groups are blocked by complex formation the bitterness of the drug reduces drastically. A drug-resin complex is made from the bitter drugs and ion-exchange resins. The nature of the drug-resin complex is such that the average pH of 6.7 and cation concentration of about 40 meq/ lit in saliva are not able to break the drugresin complex but it is weak enough to be broken down by the hydrochloric acid present in the stomach. Thus the drug: resin complex is absolutely tasteless and stable, with no after taste, but at the same time its bioavailability is not affected. Ion exchange resin like Amberlite was used to formulate taste masked fast dissolving orally consumable films of dextromethorphan (cough suppressant drug) [33,34]; (7) inclusion complexes in which the drug molecule fits into the cavity of a complexing agent forming a stable complex. The obtained complexing agent has the potential to mask the bitter taste of a drug by either decreasing its oral solubility on ingestion, or decreasing the amount of drug particles exposed to taste buds, thus reducing the perception of bitter taste. The inclusion com‐ plexes with cyclodextrin owe their existence to van der Waals forces between the host and guest. Cyclodextrin is the most widely used complexing agent for inclusion type com‐ plexes. It is a sweet, nontoxic, cyclic oligosaccharide derived from starch. Cyclodextrin forms inclusion complexes with organic molecules both in solid state and in solution [35]; (8) pH modifiers are capable of generating a specific pH microenvironment in aqueous media that has the ability to facilitate *in situ* precipitation of the bitter drug compound in saliva thus reducing the overall taste sensation for liquid dosage forms like suspension [36]; (9) adsorbates which are commonly used with other taste masking technologies to mask pharmaceuticals bitterness. The pharmaceutical may be adsorbed or/and entrapped in the matrix of the adsorbate porous, which may result in a delayed release of the bitter tastant during the passage through the oral cavity and hence achieving taste masking [37]; (10) chemicals; the solubility and absorption of drugs can be modified by the formation of molecular complexes. Lowering drug solubility through molecular complexation can decrease the intensity of bitterness. Higuchi and Pitman [38] reported that caffeine (**22**) (Figure 3) forms complexes with organic acids that are less soluble than xanthenes and as such can be used to decrease the bitter taste of caffeine; (11) solid dispersions; solid dispersion have been defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting (fusion) solvent or melting solvent method. Solid dispersion is also called as co precipitates for those preparation obtained by solvent method such as co precipitates of sulphathiazole (**23**) (Figure 3) and povidone. Solid dispersions using insoluble matrices or bland matrices may be used to mask the bitter taste of drugs. Also using them as absorbates on various carriers may increase the stability of certain drugs [39]; (12) multiple emulsions; a novel technique for taste masking of drugs employing multiple emulsions has been prepared by dissolving drug in the inner aque‐ ous phase of w/o/w emulsion under conditions of good shelf stability. The formulation is designed to release the drug through the oil phase in the presence of gastrointestinal fluid [40]; (13) using liposomes is another way of masking the unpleasant taste of therapeutic agent is to entrap them into liposome. For example, incorporating it into a liposomal

ing techniques. It is more efficient technology for aggressively bitter drugs even though coating imperfections, if present, reduce the efficiency of the technique. Coating of tablets, pellets or any other kind of particles with a film-forming polymer is a successful ap‐ proach to provide a physical barrier, concealing unpleasant odors and bitter taste. Addition‐ ally, it can prevent penetration of moisture into the formulation. Coating materials can be selected from a wide range of hydrophobic and hydrophilic polymers such as polyvinylpyr‐ rolidone, polyvinyl alcohol and cellulose derivatives. The ideal polymer for taste-mask‐ ing, odor suppression and moisture protection should prevent dissolution of the dosage form in the mouth, but should be readily soluble in the stomach. Coating is classified based on the type of coating material, coating solvent system, and the number of coating layers. Taste masked famotidine (a drug for ulcer treatment) formulated by using a combination of water soluble polymers like polyvinylpyrrolidone and insoluble polymers like cellulose acetate is an example of such technique. Other various inert coating agents can be used to coat bitter drugs. These coating agents simply provide a physical barrier over the drug particles. Examples for such coating agents are starch, povidone, gelatin, methylcellulose, ethyl cellulose and etc. One of the most efficient Method of drug particle coating is the fluidized bed processor [4]. In this approach, powders as fine as 50 um are fluidized in an 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 a spray through a nozzle. Increasing the length of the coating cycle can increase coating thickness. Taste masking of Ibuprofen (**16**)(Figure 2) has been successfully achieved by this technique [4]; (4) microen‐ capsulation is a technique applicable to protect materials from oxidation, volatilizing as well as to mask their bitter tastes [6]. Microencapsulation processes are commonly based on the principle of solvent extraction or evaporation. Microencapsulation as a process has been defined by Bakan [6] as a means of applying relatively thin coating to small parti‐ cles of solid, droplets of liquid and dispersion. This process can be used for masking the bitter taste of drugs by 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 be first encapsulated to produce free flowing microcapsules, which are then blended with other excipients and com‐ pressed into tablets. Microencapsulation also increases the stability of the drug. It can be accomplished by a variety of methods, including air suspension, coacervation-phase separation, spray drying and congealing, pan coating, solvent evaporation and multiorifice centrifugation techniques; (5) taste suppressants and potentiators such as the Linguagen's bitter blockers (e.g. adenosine monophosphate) are used for masking bitter taste of various compounding by competing with the latter on binding to the G-protein coupled receptor sites (GPCR) [32]; (6) ion exchange resins are water insoluble, crosslinked polymers containing salt forming groups in repeating position on the polymer chain. Drug can be bound to the ion exchange resin by either repeated exposure of the resin to the drug in a chromatographic column or by prolonged contact of resin with the drug solution. The resins forms insoluble adsorbates or resinates through weak ionic bonding with oppositely charged drugs. The exchange of counter ions from resin is competitive.

404 Application of Nanotechnology in Drug Delivery

**T**

formulation prepared with egg phosphatidyl choline masked the bitter taste of an antima‐ larial, chloroquine phosphate(**24**) (Figure 4)in HEPES (N-2-hydroxyetylpiperzine-N'-2 ethane sulfonic acid) buffer at pH 7.2 [41];and (14) prodrugs; chloramphenicol palmitate ester (**25**) (Figure 4), clindamycin palmitate ester (**26**) (Figure 4)and triamcinolone diace‐ tate ester (**27**)(Figure 4) [42].

Although the mentioned approaches have helped to improve the taste of some drugs formulations, the problem of the bitter taste of drugs in pediatric and geriatric formula‐ tions still creates a serious challenge to pharmacists. Thus, different strategies should be developed in order to overcome this serious problem. The novel chemical approach discussed in this chapter involves the design of prodrugs for masking bitter taste of pharmaceuticals based on intramolecular processes using density functional theory (DFT) and ab initio methods [43] and correlations of experimental and calculated reactions rates. No enzyme is needed to catalyze the interconversion of a prodrug to its corresponding

**H2N**

**N**

**S O**

**O**

**H2N**

**N**

**Celecoxib (18)**

**O**

**F**

**N**

**N**

**H3C H**

**O**

**N**

**O**

**HO**

**O**

**O**

**Caffeine (22)**

**Figure 3.** Chemical Structures for **18**-**23**.

**Levofloxacin (20)**

**<sup>N</sup> <sup>N</sup>**

**N**

**CF3**

**N CH3** **N**

**Etoricoxib (19)**

Prodrugs for Masking the Bitter Taste of Drugs

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

**S**

**O**

**O**

**O**

**O**

**NH**

**Sulfathiazole (23)**

**N**

**S**

**N**

**S O**

**O**

**H**

**O**

**Talampicillin (21)**

**H N**

**O**

**NH2**

**N**

**Cl**

407

**S O**

**H3C**

**O**

**Figure 2.** Chemical structures for **10**-**17**.

**N**

formulation prepared with egg phosphatidyl choline masked the bitter taste of an antima‐ larial, chloroquine phosphate(**24**) (Figure 4)in HEPES (N-2-hydroxyetylpiperzine-N'-2 ethane sulfonic acid) buffer at pH 7.2 [41];and (14) prodrugs; chloramphenicol palmitate ester (**25**) (Figure 4), clindamycin palmitate ester (**26**) (Figure 4)and triamcinolone diace‐

**N**

**Fexofenadine (11)**

**OH**

**Salbutamol (13)**

**NH2**

**O**

**Amoxicillin (15)**

**N**

**Quinine (17)**

**OCH3**

**HN**

**N**

**H**

**O**

**OH**

**N**

**H N**

**S**

**O**

**OH**

**OH <sup>O</sup>**

**OH**

**OH**

tate ester (**27**)(Figure 4) [42].

406 Application of Nanotechnology in Drug Delivery

**OH**

**HO**

**erfenedine (10)**

**H**

**H**

**Prednisolone (12)**

**O**

**Figure 2.** Chemical structures for **10**-**17**.

**OH**

**O**

**O OH OH**

**OH**

**O**

**HO**

**H**

**Guaifenesin (14)**

**Ibuprofen (16)**

**OH**

**HO**

**HO**

**HO**

**N**

**T**

**O**

**Celecoxib (18)**

**Levofloxacin (20)**

**Etoricoxib (19)**

**Talampicillin (21)**

**Figure 3.** Chemical Structures for **18**-**23**.

Although the mentioned approaches have helped to improve the taste of some drugs formulations, the problem of the bitter taste of drugs in pediatric and geriatric formula‐ tions still creates a serious challenge to pharmacists. Thus, different strategies should be developed in order to overcome this serious problem. The novel chemical approach discussed in this chapter involves the design of prodrugs for masking bitter taste of pharmaceuticals based on intramolecular processes using density functional theory (DFT) and ab initio methods [43] and correlations of experimental and calculated reactions rates. No enzyme is needed to catalyze the interconversion of a prodrug to its corresponding

drug. The rate of drug release is controlled by the nature of the linker bound to the drug. Bitter tastant molecules interact with taste receptors on the tongue to give bitter sensa‐ tion. Altering the ability of the drug to interact with bitter taste receptors could reduce or eliminate its bitterness. This could be achieved by an appropriate modification of the structure and the size of a bitter compound. Bitter molecules bind to the G-protein coupled receptor-type T2R on the apical membrane of the taste receptor cells located in the taste buds [44,45].

lin (**15**) (Figure 2) and cephalexin (**31**) (Figure 4) [56]. The role of the promoiety in the antibacterial (cefuroxime) prodrugs is to block the free amine or the hydroxyl group which is responsible for the drug bitter taste, and to enable the release of a drug in a programma‐ ble manner. The only difference between the proposed prodrugs and their parent drugs is that the amine group in the parent drug is replaced with an amide moiety. Replacing the amine group with an amide eliminate the capability of the molecule to hydrogen bond with the bitter taste receptor, thus masking the bitter taste of the parent drug. For example, paracetamol, a widely used pain killer and fever-reducer found in the urine of patients who had taken phenacetin (**32**) (Figure 4) has a very unpleasant bitter taste. Phenacetin, on the other hand, lacks or has very slight bitterness. The difference in the structural features of both drugs is only in the nature of the group in the *para* position of the benzene ring. While in the case of paracetamol the group is hydroxyl, in phenacetin it is ethoxy. Acetanilide (**33**) (Figure 4) has a chemical structure similar to that of paracetamol and phenacetin but lacks the group in the *para* position of the benzene ring, making it lack the bitter taste characteristic of paracetamol. These combined facts suggest that the presence of the hydroxy group on the *para* position of paracetamol is the major contributor for its bitter taste. It is believed that paracetamol interacts with the bitter taste receptors *via* hydrogen bonding which involves its phenolic group. Blocking the phenolic hydroxyl of paracetamol is expected to inhibit its binding to the bitter taste receptor and hence to eliminate its bitterness. Similarly, it is expected that blocking the free amine group in atenolol, amoxicil‐ lin or cephalexin with a suitable linker might inhibit the interaction between the amine group of the parent drug and its bitter taste receptors and hence masks its bitterness. The nature of the bitter taste receptors with paracetamol (via the phenolic group) or atenolol, amoxicillin or cephalexin (via the amine group) is likely to be as a result of hydrogen

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409

In this chapter, the novel prodrug approach to be presented is based on enzyme models that have been made to understand the mechanism by which enzymes catalyze biochemical reactions. The tool exploited in the design is computational calculations using molecular orbital and molecular mechanics methods and correlations between experimental and calculated rate values for some intramolecular processes. In this approach, no enzyme is needed to catalyze the conversion of a prodrug to its active parent drug. The conversion rate is solely determined by the factors affecting the rate limiting step in the intramolecular (conversion) process. Knowledge gained from the mechanisms of the previously studied

It is believed that the use of this approach might eliminate all disadvantages related to prodrug conversion by the metabolic (enzyme catalyzed process) approach. The bioconversion of prodrugs is perhaps the most vulnerable link in the chain, because there are many intrinsic and extrinsic factors that can affect the process. For example, the activity of many prodrug activating enzymes may be varied due to genetic polymorphisms, age-related physiological changes, or drug interactions, leading to adverse pharmacokinetic, pharmacodynamic, and clinical effects. In addition, there are wide interspecies variations in both the expression and

bonding between the substrate and the receptor.

enzyme models was exploited in the design.

Due to the large variation of structural features of bitter tasting molecules, it is difficult to generalize the molecular requirements for bitterness. Nevertheless, it was reported that a bitter tastant molecule requires a polar group and a hydrophobic moiety. A quantitative structure activity relationship (QSAR) model was developed and has been established for the prediction of bitterness of several tastant analogues. For example, it was reported that the addition of a pyridinium moiety to an amino acid chain of a variety of bitter amino acid compounds decreases bitterness, such as in the case of glycine. Other structural modifications, such as an increase in the number of amino groups/residues to more than 3 and a reduction in the poly-hydroxyl group/ COOH, have been proven to decrease bitterness significantly. Moreover, changing the configuration of a bitter tastant molecule by mak‐ ing isomer analogues was found to be important for binding affinity to enhance bitter‐ ness agonist activity (e.g. L-tryptophan is bitter while D-tryptophan is sweet) [46].

Our recent studies on intramolecularity have demonstrated that there is a necessity to further explore the mechanisms for the intramolecular processes to be utilized in the design for determining the factors playing dominant role in determining the reaction rate. Unraveling the reaction mechanism would allow for an accurate design of an efficient chemical device to be used as a prodrug linker that can be covalently linked to a drug which can chemically, and not enzymatically be cleaved to release the active parent drug in a controlled manner. For instance, exploring the mechanism for a proton transfer in Kirby's acetals [47] has led to a design and synthesis of novel prodrugs of aza-nucleo‐ sides to treat myelodysplastic syndromes [48] and statins to treat high cholesterol levels in the blood [49]. In the above mentioned examples, the prodrug moiety was attached to the hydroxyl group of the active drug such that the drug promoiety (prodrug) has the potential to degrade upon exposure to physiological environment such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby's enzyme model). Other different linkers such as Kirby's maleamic acid enzyme model [50] was also investigated for the design of some prodrugs such as tranexamic acid prodrugs to treat bleeding conditions [51] and acyclo‐ vir as anti-viral drug to treat Herpes Simplex [52]. Menger's Kemp acid enzyme model [53] was also utilized for the design of dopamine prodrugs for the treatment of Parkinson's disease [54]. Prodrugs for dimethyl fumarate to treat psoriasis were also designed, synthesized and currently under *in vitro* and *in vivo* kinetic studies [55].

The same approach was utilized for masking the bitter taste of antibacterial drugs such as cefuroxime (**28**) (Figure 4), atenolol (**29**) (Figure 4), paracetamol (**30**) (Figure 4), amoxicil‐ lin (**15**) (Figure 2) and cephalexin (**31**) (Figure 4) [56]. The role of the promoiety in the antibacterial (cefuroxime) prodrugs is to block the free amine or the hydroxyl group which is responsible for the drug bitter taste, and to enable the release of a drug in a programma‐ ble manner. The only difference between the proposed prodrugs and their parent drugs is that the amine group in the parent drug is replaced with an amide moiety. Replacing the amine group with an amide eliminate the capability of the molecule to hydrogen bond with the bitter taste receptor, thus masking the bitter taste of the parent drug. For example, paracetamol, a widely used pain killer and fever-reducer found in the urine of patients who had taken phenacetin (**32**) (Figure 4) has a very unpleasant bitter taste. Phenacetin, on the other hand, lacks or has very slight bitterness. The difference in the structural features of both drugs is only in the nature of the group in the *para* position of the benzene ring. While in the case of paracetamol the group is hydroxyl, in phenacetin it is ethoxy. Acetanilide (**33**) (Figure 4) has a chemical structure similar to that of paracetamol and phenacetin but lacks the group in the *para* position of the benzene ring, making it lack the bitter taste characteristic of paracetamol. These combined facts suggest that the presence of the hydroxy group on the *para* position of paracetamol is the major contributor for its bitter taste. It is believed that paracetamol interacts with the bitter taste receptors *via* hydrogen bonding which involves its phenolic group. Blocking the phenolic hydroxyl of paracetamol is expected to inhibit its binding to the bitter taste receptor and hence to eliminate its bitterness. Similarly, it is expected that blocking the free amine group in atenolol, amoxicil‐ lin or cephalexin with a suitable linker might inhibit the interaction between the amine group of the parent drug and its bitter taste receptors and hence masks its bitterness. The nature of the bitter taste receptors with paracetamol (via the phenolic group) or atenolol, amoxicillin or cephalexin (via the amine group) is likely to be as a result of hydrogen bonding between the substrate and the receptor.

drug. The rate of drug release is controlled by the nature of the linker bound to the drug. Bitter tastant molecules interact with taste receptors on the tongue to give bitter sensa‐ tion. Altering the ability of the drug to interact with bitter taste receptors could reduce or eliminate its bitterness. This could be achieved by an appropriate modification of the structure and the size of a bitter compound. Bitter molecules bind to the G-protein coupled receptor-type T2R on the apical membrane of the taste receptor cells located in the taste

Due to the large variation of structural features of bitter tasting molecules, it is difficult to generalize the molecular requirements for bitterness. Nevertheless, it was reported that a bitter tastant molecule requires a polar group and a hydrophobic moiety. A quantitative structure activity relationship (QSAR) model was developed and has been established for the prediction of bitterness of several tastant analogues. For example, it was reported that the addition of a pyridinium moiety to an amino acid chain of a variety of bitter amino acid compounds decreases bitterness, such as in the case of glycine. Other structural modifications, such as an increase in the number of amino groups/residues to more than 3 and a reduction in the poly-hydroxyl group/ COOH, have been proven to decrease bitterness significantly. Moreover, changing the configuration of a bitter tastant molecule by mak‐ ing isomer analogues was found to be important for binding affinity to enhance bitter‐

ness agonist activity (e.g. L-tryptophan is bitter while D-tryptophan is sweet) [46].

synthesized and currently under *in vitro* and *in vivo* kinetic studies [55].

The same approach was utilized for masking the bitter taste of antibacterial drugs such as cefuroxime (**28**) (Figure 4), atenolol (**29**) (Figure 4), paracetamol (**30**) (Figure 4), amoxicil‐

Our recent studies on intramolecularity have demonstrated that there is a necessity to further explore the mechanisms for the intramolecular processes to be utilized in the design for determining the factors playing dominant role in determining the reaction rate. Unraveling the reaction mechanism would allow for an accurate design of an efficient chemical device to be used as a prodrug linker that can be covalently linked to a drug which can chemically, and not enzymatically be cleaved to release the active parent drug in a controlled manner. For instance, exploring the mechanism for a proton transfer in Kirby's acetals [47] has led to a design and synthesis of novel prodrugs of aza-nucleo‐ sides to treat myelodysplastic syndromes [48] and statins to treat high cholesterol levels in the blood [49]. In the above mentioned examples, the prodrug moiety was attached to the hydroxyl group of the active drug such that the drug promoiety (prodrug) has the potential to degrade upon exposure to physiological environment such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby's enzyme model). Other different linkers such as Kirby's maleamic acid enzyme model [50] was also investigated for the design of some prodrugs such as tranexamic acid prodrugs to treat bleeding conditions [51] and acyclo‐ vir as anti-viral drug to treat Herpes Simplex [52]. Menger's Kemp acid enzyme model [53] was also utilized for the design of dopamine prodrugs for the treatment of Parkinson's disease [54]. Prodrugs for dimethyl fumarate to treat psoriasis were also designed,

buds [44,45].

408 Application of Nanotechnology in Drug Delivery

In this chapter, the novel prodrug approach to be presented is based on enzyme models that have been made to understand the mechanism by which enzymes catalyze biochemical reactions. The tool exploited in the design is computational calculations using molecular orbital and molecular mechanics methods and correlations between experimental and calculated rate values for some intramolecular processes. In this approach, no enzyme is needed to catalyze the conversion of a prodrug to its active parent drug. The conversion rate is solely determined by the factors affecting the rate limiting step in the intramolecular (conversion) process. Knowledge gained from the mechanisms of the previously studied enzyme models was exploited in the design.

It is believed that the use of this approach might eliminate all disadvantages related to prodrug conversion by the metabolic (enzyme catalyzed process) approach. The bioconversion of prodrugs is perhaps the most vulnerable link in the chain, because there are many intrinsic and extrinsic factors that can affect the process. For example, the activity of many prodrug activating enzymes may be varied due to genetic polymorphisms, age-related physiological changes, or drug interactions, leading to adverse pharmacokinetic, pharmacodynamic, and clinical effects. In addition, there are wide interspecies variations in both the expression and

**5. Enzyme models utilized for the design of potential bitterless prodrugs for bitter drugs such as atenolol, amoxicillin, cephalexin, paracetamol and**

Prodrugs for Masking the Bitter Taste of Drugs

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

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Scholar studies of enzyme mechanisms by several chemists and biochemists, over the past five decades, have had a significant contribution for understanding the mode and scope of enzymes

Nowadays, the scientific community has reached to the conclusion that enzyme catalysis is based on the combined effects of the catalysis by functional groups and the ability to reroute intermolecular reactions through alternative pathways by which substrates can bind to preorganized active sites. It is believed that rate accelerations by enzymes can be proceed by (i) covalently enforced proximity, as seen in the case of chymotrypsin, [57] (ii) non-covalently enforced proximity, as represented in the catalysis of metallo-enzymes, [58] (iii) covalently enforced strain, [59], and (iv) non-covalently enforced strain, which has been extensively studied on models mimicking the lysozyme enzyme which is most closely associated with rate

Rates for the majority of enzymatic reactions ranges between 1010 and 1018 fold their nonenzymatic bimolecular counterparts. For instance, biochemical reactions involving the catalysis of the enzyme cyclophilin are enhanced by105 and those by the enzyme oroti‐ dine monophosphate decarboxylase are accelerated by 1017 [61]. The significant enhance‐ ment in rate manifested by enzymes is a result of the substrate binding within the confines of the enzyme active site. The substrate-enzyme binding energy is the dominant driving force and the major contributor to catalysis. A consensus has been reached that in all enzymatic processes binding energy is used to overcome physical and thermodynamic factors that make barriers to the reaction (free energy). These factors are: (1) the change in entropy (ΔS˚), in the form of the freedom of motions of the reactants in solution; (2) the hydrogen bonding net around bio-molecules in aqueous solution; (3) a proper alignment of catalytic functional groups on the enzyme; and (4) the distortion of a substrate that must

Scholarly studies have been done by Bruice, Cohen, Menger, Kirby and others to design enzyme models having the potential to reach rates comparable to rates of biochemical reactions catalyzed by enzymes. Examples for such models are those based on rate enhancements driven by covalently enforced proximity. The most cited example is the intramolecular cyclization of dicarboxylic semi esters to anhydrides advocated by Bruice *et al.*[64,65]. Bruice et al. has demonstrated that a relative rate of anhydride formation can reach 5 x 107 upon cyclization of a dicarboxylic semi ester when compared to a similar counterpart's bimolecular process.

Other examples of rate acceleration based on proximity orientation include: (a) acid-catalyzed lactonization of hydroxy-acids as studied by Cohen et al.[66-68] and Menger [63, 69-75], (b) intramolecular SN2-based cyclization reactions as researched by Brown et al. [76] and Mando‐ lini's group [77], (c) proton transfer between two oxygens in Kirby's acetals [78-84], and proton transfer between nitrogen and oxygen in Kirby's enzyme models [78-84], (d) proton transfer

**guaiphenesin**

acceleration due to this kind of strain [60].

occur before the reaction takes place [62,63].

catalysis.

function of the major enzymes activating prodrugs, and these can pose some obstacles in the preclinical optimization phase.
