**11. Bitterless amoxicillin and cephalexin prodrugs based on Kirby's maleamic acids enzyme model**

Most of the antibacterial agents that are commonly used suffer unpleasant taste and a respected number of them are characterized with bitter taste. For example, amoxicillin, cephalexin and cefuroxime axetil have an extremely unpleasant and bitter taste which is difficult to mask. This is a particular problem in geriatric patients who cannot swallow whole tablets or when small doses are required. Even the antibacterial suspension is difficult for pediatrics to administer due to its better and unpleasant taste [133-139].

It is widely assumed that the extremely bitter and unpleasant taste of these antibacterial drugs is due to a formation of intermolecular force/s between the drug and the active site of the bitter taste receptor/s. The intermolecular bond/s is/are most likely due to formation either *via* hydrogen bond or ionic bond of the amido (in cefuroxime)or amine (in amoxicillin and cephalexin) group to the active site of the bitter taste receptors.

Antimicrobial agents are classified according to their specific mode of action against bacterial cell. By which these agents may interfere with cell wall synthesis, inhibit protein synthesis, interfere with nucleic acid synthesis or inhibit a metabolic pathway. They have a broad spectrum of activity against both gram-positive and gram-negative bacteria. Among these agents, β-lactams – penicillins, cephalosporins, carbapenems and monobactams, by which represent 60% of all antimicrobial use by weight. They are preferred because of their efficacy, safety, and because their activity can be extended or restored by chemical manipulation. Inevitably, however, their usage has been restricted because of their bacterial resistance.

#### **11.1. Amoxicillin**

Amoxicillin is an oral semi-synthetic penicillin, moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms by which it is susceptible to the action of the β-lactamases. Amoxicillin has a bactericidal action and acts against both Gram positive and Gram-negative microorganisms by inhibiting the biosynthesis and repair of the bacterial mucopeptide wall. It is usually the drug of choice within its class because it is well absorbed following oral administration. Amoxicillin presents some out‐ standing advantages in comparison with other amino-penicillins, such as: a better absorption from the intestinal tract, better capacity for reaching effective concentrations at the sites of action and a more rapid capacity for penetrating the cellular wall of Gram-negative microor‐ ganisms. Amino-penicillins are frequently prescribed agents for the oral treatment of lower respiratory tract infections and are generally highly effective against S. pneumonia and nonβ-lactamase-producing H. influenza. Amoxicillin is mostly common antibiotics prescribed for children. It has high absorption after oral administration which is not altered and affected by the presence of food. Amoxicillin dose reaches Cmax about 2 hours after administration and is quickly distributed and eliminated by excretion in urine (about 60%-75%). The antibacterial effect of amoxicillin is extended by the presence of a benzyl ring in the side chain. Because amoxicillin is susceptible to degradation by β-lactamase-producing bacteria, which are resistant to a broad spectrum of β-lactam antibiotics, such as penicillin, for this reason, it is often combined with clavulanic acid, a β-lactamase inhibitor. This increases effectiveness by reducing its susceptibility to β-lactamase resistance. Amoxicillin has two ionizable groups in the physiological range (the amino group in α-position to the amide carbonyl group and the carboxyl group). Amoxicillin has a good pharmacokinetics profile with bioavailability of 95% if taken orally, its half-life is 61.3 minutes and it is excreted by the renal and less than 30 % biotransformed in the liver [140-142].

#### **11.2. Cephalexin**

**t 1/2 (h) k obs (h-1) Medium** 2.53 4.95 x 10 -4 1 N HCl 3.82 2.22 x 10 -4 Buffer pH 2 133 2.75 x 10-6 Buffer pH 5 ----- No Reaction Buffer pH 7.4

**11. Bitterless amoxicillin and cephalexin prodrugs based on Kirby's**

Most of the antibacterial agents that are commonly used suffer unpleasant taste and a respected number of them are characterized with bitter taste. For example, amoxicillin, cephalexin and cefuroxime axetil have an extremely unpleasant and bitter taste which is difficult to mask. This is a particular problem in geriatric patients who cannot swallow whole tablets or when small doses are required. Even the antibacterial suspension is difficult for pediatrics to administer

It is widely assumed that the extremely bitter and unpleasant taste of these antibacterial drugs is due to a formation of intermolecular force/s between the drug and the active site of the bitter taste receptor/s. The intermolecular bond/s is/are most likely due to formation either *via* hydrogen bond or ionic bond of the amido (in cefuroxime)or amine (in amoxicillin and

Antimicrobial agents are classified according to their specific mode of action against bacterial cell. By which these agents may interfere with cell wall synthesis, inhibit protein synthesis, interfere with nucleic acid synthesis or inhibit a metabolic pathway. They have a broad spectrum of activity against both gram-positive and gram-negative bacteria. Among these agents, β-lactams – penicillins, cephalosporins, carbapenems and monobactams, by which represent 60% of all antimicrobial use by weight. They are preferred because of their efficacy, safety, and because their activity can be extended or restored by chemical manipulation. Inevitably, however, their usage has been restricted because of their bacterial resistance.

Amoxicillin is an oral semi-synthetic penicillin, moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms by which it is susceptible to the action of the β-lactamases. Amoxicillin has a bactericidal action and acts against both Gram positive and Gram-negative microorganisms by inhibiting the biosynthesis and repair of the bacterial mucopeptide wall. It is usually the drug of choice within its class because it is well absorbed following oral administration. Amoxicillin presents some out‐ standing advantages in comparison with other amino-penicillins, such as: a better absorption

In 1N HCl and at pH 2, 5 and 7.4

422 Application of Nanotechnology in Drug Delivery

**11.1. Amoxicillin**

**Table 1.** The observed k value and t1/2 of atenolol **ProD 1**

due to its better and unpleasant taste [133-139].

cephalexin) group to the active site of the bitter taste receptors.

**maleamic acids enzyme model**

Cephalexin is a first-generation cephalosporin antibiotic, which was chosen as the model drug candidate to obtain dosage with improved stability, palatability and attractive pediatric elegance, cost effective with ease of administration. Cephalosporins are the most widely used for treatment of skin infections because of their safety profile, and their wide range of activity against both gram positive and gram negative microorganism. Cephalexin is also used for the treatment of articular infections as a rational first-line treatment for cellulitis, it is a useful alternative to penicillins hypersensitivity, and thought to be safe in a patient with penicillin allergy but caution should always be taken, that's because cephalexin and other first-genera‐ tion cephalosporins are known to have a modest cross-allergy in patients with penicillin hypersensitivity. In addition, cephalexin is also effective and used in the treatment of group A β-hemolytic streptococcal throat infections. Cephalexin works by interfering with the bacter‐ ia's cell wall formation, causing it to rupture, and thus killing the bacteria. The compound is zwitterionbywhichitcontainsbothabasicandanacidicgroup,theisoelectricpointofcephalexin in water is approximately 4.5 to 5. Cephalexin has a good pharmacokinetic profile by which it is well absorbed, 80% excreted unchanged in urine within 6 hours of administration. Cephalex‐ in'shalf-life is0.5-1.2hoursanditis excreted*via* the renal.Itisusedforthe treatmentofinfections includingotitismedia,streptococcalpharyngitis,boneandjointinfections,pneumonia,cellulitis and UTI, and so it may be used to prevent bacterial endocarditis [142-145].

#### **11.3. Cefuroxime axetil**

Cefuroxime axetil is a semi-synthetic, broad-spectrum cephalosporin antibiotic for oral administration. Cefuroxime axetil is an orally active antibacterial agent though its absorption is incomplete. The range of its bioavailability is 25-52%. The axetil moiety is metabolized to acetaldehyde and acetic acid. Peak plasma concentration is reached 2-3 hours after an oral administration. Up to 50% of cefuroxime in the circulation is bound to plasma proteins. The plasma half-life is about 70 minutes and is prolonged in patients with renal impairments and in neonates. Cefuroxime axetil is widely distributed in the body including plural fluid, sputum bone synovial fluid, and aqueous humor, but only achieves therapeutic concentration in the CSF when the meninges are inflamed. It crosses the placenta and has been detected in breast milk. Cefuroxime is excreted unchanged, by glomerular filtration and renal tubular secretion, and high concentration is achieved in urine [146].

lipophilic prodrugs have poor solubility in gastric fluids and thus greater stability and

Some ampicillin esters were prepared for improving the bioavailability of ampicillin. For example, the pivaloyloxyethyl (pivampicillin), phthalidyl (talampicillin), and ethoxycarbony‐ loxyethyl (bacampicillin)were found to have two fold the oral bioavailability of their parent drug, ampicillin. Complete hydrolysis of these esters was occurred in the gastrointestinal mucosa,whereasmethoxymethylesterofampicillinwaspartiallyhydrolyzedbygutandhepatic first-passmetabolismandappearsinthesystemiccirculationandtissuesasintactester[151-154].

**12. In vitro intraconversion of amoxicillin and cephalexin prodrugs to their**

Based on our previously reported DFT calculations and on experimental data for the acidcatalyzed hydrolysis of amide acids **34**-**42** (Figure 5) [84,91], two amoxicillin and cephalexin prodrugs were proposed (Figures11 and 12, respectively). As shown in Figures11 and 12, the antibacterial prodrugs, amoxicillin **ProD 1** and cephalexin **ProD 1** molecules are composed of an amide acid promoiety, containing a carboxylic acid group (hydrophilic moiety) and the rest

**N**

**H**

**O**

**O**

**NH2**

**HO**

**O**

**O**

**O**

**Amoxicillin ProD 1 Maleic anhydride Amoxicillin**

The combination of both, the hydrophilic and lipophilic groups provides a prodrug entity with a potential to be with a high permeability (a moderate HLB). It should be emphasized, that the HLB value of the prodrug entity will be determined upon the pH of the target physiological environment. In the stomach where the pH is in the range 1-2, it is expected that prodrugs, amoxicillin **ProD1** and cephalexin **ProD1** will be in a free carboxylic acid form (a relatively high hydrophobicity) whereas in the blood stream circulation where the is pH 7.4 a carboxylate anion (a relatively low hydrophobicity) is expected to be predominant form. Our strategy was to prepare amoxicillin **ProD 1** and cephalexin **ProD 1** as sodium or potassium carboxylates due to their high stability in neutral aqueous medium. It should be indicated that compounds

**H N**

Prodrugs for Masking the Bitter Taste of Drugs

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

425

**S**

**O**

**OH**

absorption example for such approach is erythromycin esters [150].

of the antibacterial prodrug molecule (a lipophilic moiety). **<sup>N</sup>**

**S**

**H**

**O**

**OH**

**H2O**

**O**

**Figure 11.** Acid-catalyzed hydrolysis of amoxicillin ProD 1.

**O**

**HN**

**OH**

**O**

**HO**

**H N**

**O**

**parent drugs**

Amoxicillin, cephalexin and cefuroxime axetil as mentioned before suffer low stability and bitter taste sensation. Several attempts were made in order to enhance their aqueous solubility and bioavailability. Among several research approaches, the prodrug approach has been widely used for an improvement of drugs delivery to their site of action by physicochemical modulation properties that affect absorption or by targeting to specific enzymes or membrane transporters [147,148]. Generally, enzymatic catalysis is required for most of prodrugs that are in clinical use in order to be converted into the parent drug. This is mostly particular for those prodrugs designed to liberate the parent drug in the blood stream following gastro-intestinal absorption. These prodrugs are typically ester derivatives of drugs containing carboxyl or hydroxyl groups which are converted into the parent drug by esterase catalyzed hydrolysis. However, a high chemical reactivity that precludes either liquid or solid formulation of the prodrug (e.g. some phenol esters) or low chemical reactivity, resulting in reduced regeneration of the parent drug due to enzymatic activation for other functional groups. Thus, nonenzymatic pathways for some prodrugs that can regenerate the parent drug, have emerged as an alternative approach by which prodrug activation is not influenced by inter-and intraindividual variability that affects the enzymatic activity. In particular, since the middle-1980s, cyclization-activated prodrugs have been capturing the attention of medicinal chemists, and reached maturity in prodrug design in the late 1990s. Activation of prodrugs *via* a cyclization pathway allows a fine tuning of the rate of drug release through the appropriate choice of the functional groups involved in ring closure and stereoelectronic constraints in the course of the cyclization step. As noticed from the history of prodrugs mostly in preclinical and clinical consideration of prodrug bioconversion, the most common that several hydrolyses-activated prodrugs of penicillins, cephalosporins, and angiotensin-converting enzyme inhibitors have less than complete absorption which was observed and highlights yet another challenge with prodrugs susceptible to esterase hydrolysis. The oral bioavailability of these mentioned types of prodrugs is typically around 50% since these prodrugs undergo premature hydrolysis during the absorption process in the enterocytes of the gastrointestinal tract [149]. Another approach which has been utilized to enhance bioavailability of antibacterial drugs is by making the corresponding prodrugs with optimum lipophilicity. Some drugs remain poorly absorbed from most of the administration routes due to their poor lipophilicity. Two approaches were utilized to enhance the bioavailability of antibacterial drugs by increasing their lipophilicity: (a) membrane/water partition coefficient of the lipophilic form of a drug has been enhanced as compared to the hydrophilic form, thus favoring passive diffusion such as in the cases of pivampicillin, bacampicillin and talamipicillin (prodrugs of ampicillin)which are more lipophilic and better absorbed than amoxicillin and are rapidly interconverted and (b) the lipophilic prodrugs have poor solubility in gastric fluids and thus greater stability and absorption example for such approach is erythromycin esters [150].

Some ampicillin esters were prepared for improving the bioavailability of ampicillin. For example, the pivaloyloxyethyl (pivampicillin), phthalidyl (talampicillin), and ethoxycarbony‐ loxyethyl (bacampicillin)were found to have two fold the oral bioavailability of their parent drug, ampicillin. Complete hydrolysis of these esters was occurred in the gastrointestinal mucosa,whereasmethoxymethylesterofampicillinwaspartiallyhydrolyzedbygutandhepatic first-passmetabolismandappearsinthesystemiccirculationandtissuesasintactester[151-154].
