Taste masking of bitter drugs pdf

Drewnoswki A The science and complexity of bitter taste. Nutr Rev 59 6 — Article Google Scholar. Am J Clin Nutr 72 6 — Eckert M, Riker P Overcoming challenges in functional beverages. Food Technol — Fujii K, Yasuda A Improving of food taste by adding gluconic acid metal salts.

JP , in Japanese. Fujita H, Kuroki A Pharmaceutical formulations comprising sodium laurylsulfate as bitterness masking agent. EP 1,, Fuller W, Kurtz RJ a Composition comprising bitter- or metallic-tasting eatable and tastand-comprising hydroxy-, amion- or mercapto -substituted di:carboxylic acid or derivatives, especially di:peptide containing aspartic acid. US 5,, Fuller W, Kurtz RJ e Composition comprising an edible having bitter or metallic taste comprises a tastant to reduce undesired taste.

Curr Opin Neurobiol 10 4 — Green BG, Schullery MT Stimulation of bitterness by capsaicin and menthol: differences between lingual areas innervated by the glossopharyngeal and chorda tympani nerves. Chem Senses — Physiol Behav 86 4 — US 4,, Harada T, Kamada M Taste-improving agent and a food having improved taste.

US 6,, Hamisch UE, Valentin A Use of thaumatin to improve taste, reduce sweetener needs and improve pancreas function. DE 19,, in German. Hayashi N, Ujihara T, Kohata K Reduction of catechin astringency by the complexation of gallate-type catechins with pectin. Biosci Biotechnol Biochem 69 7 — J Neurosci 26 49 — Chem Sens 30 Suppl 1 :i37—i Chem Senses 19 4 — Jellinek G Moderne Verfahren der sensorischen Analyse.

Planta Medica 14 Suppl Okt. Trends Food Sci Technol — JP 02 , in Japanese. Pharm Res 12 5 — Kawabe H, Shibasaki T, Uchida T Beverage containing amino acid and method of diminishing bitterness of amino acid. WO , in Japanese. Keast RSJ The effect of zinc on human taste perception. J Food Sci 68 5 — Keast RSJ, Breslin PAS Bitterness suppression with zinc sulfate and Na-cyclamate: a model of combined peripheral and central neural approaches to flavor modification. Pharm Res 22 11 — Chimia 55 5 — Chem Senses 29 5 — Seitai No Kagaku 56 2 — Kitamura A, Uokyu T Bitterness-masking compositions and solid preparations containing them.

Kittaka R, Higashiguchi S, Yoshida Y Taste-modifying peptides, their manufacture from egg white, and use for foods and beverages. J Food Sci 67 2 — Elsevier, Amsterdam, Netherlands, pp — Chapter Google Scholar. J Neurosci 24 45 — Kurtz RJ, Fuller WD Ingestibles containing substantially tasteless sweetness inhibitors as bitter taste reducers or substantially tasteless bitter inhibitors as sweet taste reducers. In: Roy G ed Modifying bitterness.

Technomic, Basel, Switzerland, pp — US 3,, J Agric Food Chem 53 15 — Arch Pediatr Adolesc Med. Article Google Scholar. Strickley RG. Pediatric oral formulations: an updated review of commercially available pediatric oral formulations since Taste masking of paracetamol by hot-melt extrusion: An in vitro and in vivo evaluation.

Eur J Pharm Biopharm [Internet]. Available from:. Taste masking of griseofulvin and caffeine anhydrous using Kleptose Linecaps DE17 by hot melt extrusion. AAPS Pharmscitech. Orodispersible tablets containing taste-masked solid lipid pellets with metformin hydrochloride: influence of process parameters on tablet properties. Eur J Pharm Biopharm. Oral thin films as a remedy for noncompliance in pediatric and geriatric patients. Ther Deliv. Designing fast-dissolving orodispersible films of amphotericin B for oropharyngeal candidiasis.

Building process understanding of fluid bed taste mask coating of microspheres. Development and physicochemical characterization of clindamycin resinate for taste masking in pediatrics. Taste masking of azithromycin by resin complex and sustained release through interpenetrating polymer network with functionalized biopolymers.

Optimization of the factors affecting the absorption of vardenafil from oral disintegrating tablets: a clinical pharmacokinetic investigation. Int J Pharm. Taste masked thin films printed by jet dispensing. Pharm Res. Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets.

AAPS pharmscitech. Formulation and evaluation of taste-masked azithromycin Ready-Mix oral suspension. CAS Google Scholar. Ciosek P. Ab initio methods are based entirely on theory from first principles. Ab initio electronic structure methods have the advantage that they can be made to converge to the exact solution, when all approximations are sufficiently small in magnitude and when the finite set of basis functions tends toward the limit of a complete set. The convergence is usually not monotonic, and sometimes the smallest calculation gives the best result for some properties.

The disadvantage of ab initio methods is their enormous computational cost. They take a significant amount of computer time, memory, and disk space [ - ]. On the other hand, empirical or semi-empirical methods are less accurate because they employ experimental results, often from acceptable models of atoms or related molecules, to approximate some elements of the underlying theory.

Example for such methods is the semi-empirical quantum chemistry methods based on the Hartree—Fock formalism, but make many approximations and obtain some parameters from empirical data. These methods are especially important for calculating large molecules where the full Hartree—Fock method without the approximations is too expensive. Semi-empirical calculations are much faster than their ab initio counterparts.

Their results, however, can be imprecise if the molecule being computed is not similar enough to the molecules in the database used to parameterize the method. Calculations of molecules exceeding 60 atoms can be handled using semiempirical methods [ - ]. Another widely used quantum mechanical method is the density functional theory DFT. With this theory, the properties of many-electron systems can be determined by using functionals, i.

Therefore, the name density functional theory comes from the use of functionals of the electron density. DFT is among the most popular and versatile methods available in condensed-matter physics, computational physics, and computational chemistry.

The DFT method is adequate for calculating structures and energies for medium-sized systems atoms of biological, pharmaceutical and medicinal interest and is not restricted to the second row of the periodic table [ 43 ]. Although the use of DFT method is significantly increasing some difficulties still encountered when describing intermolecular interactions, especially van der Waals forces dispersion ; charge transfer excitations; transition states, global potential energy surfaces and some other strongly correlated systems.

Incomplete treatment of dispersion can adversely affect the DFT degree of accuracy in the treatment of systems which are dominated by dispersion. On the other hand, molecular mechanics is a mathematical approach used for the computation of structures, energy, dipole moment, and other physical properties. It is widely used in calculating many diverse biological and chemical systems such as proteins, large crystal structures, and relatively large solvated systems.

However, this method is limited by the determination of parameters such as the large number of unique torsion angles present in structurally diverse molecules [ ].

Molecular mechanics simulations, for example, use a single classical expression for the energy of a compound, for instance the harmonic oscillator. The database of compounds used for parameterization, i. A force field parameterized against a specific class of molecules, for instance proteins, would be expected to only have any relevance when describing other molecules of the same class. These methods can be applied to proteins and other large biological molecules, and allow studies of the approach and docking of potential drug molecules Since the size of the system which ab initio calculations can handle is relatively small despite the large sizes of biomacromolecules surrounding solvent water molecules such as in the cases of enzymes and receptors, isolated models of areas of proteins such as active sites have been investigated using ab initio calculations.

However, the disregarded proteins and solvent surrounding the catalytic centers have also been shown to contribute to the regulation of electronic structures and geometries of the regions of interest.

MM regions correspond to the remainder of the system and are treated molecular mechanically. The acid-catalyzed hydrolysis of 34 - 42 Figure 5 was kinetically investigated by Kirby et al.

The study demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is the tetrahedral intermediate breakdown Figure 6 [ 84 ].

In , the reaction was computationally investigated by Katagi using AM1 semiempirical calculations. Later on Kluger and Chin have experimentally researched the mechanism of the intramolecular hydrolysis process utilizing several N-alkylmaleamic acids derived from aliphatic amines with a wide range of basicity [ ].

The study findings demonstrated that the identity of the rate-limiting step is a function of both the basicity of the leaving group and the solution acidity. The calculations confirmed that the reaction involves three steps: 1 proton transfer from the carboxylic group to the adjacent amide carbonyl oxygen, 2 nucleophilic attack of the carboxylate anion onto the protonated carbonyl carbon; and 3 dissociation of the tetrahedral intermediate to provide products Figure 6.

Moreover, the calculations demonstrate that the rate-limiting step is dependent on the reaction medium. When the calculations were run in the gas phase the rate-limiting step was the tetrahedral intermediate formation, whereas when the calculations were conducted in the presence of a cluster of water the dissociation of the tetrahedral intermediate was the rate-limiting step.

When the leaving group methylamine in 34 - 42 was replaced with a group having a low pKa value the rate-limiting step of the hydrolysis in water was the formation of the tetrahedral intermediate. In addition, the calculations revealed that the efficiency of the intramolecular acid-catalyzed hydrolysis by the carboxyl group is remarkably sensitive to the pattern of substitution on the carbon—carbon double bond.

The rate of hydrolysis was found to be linearly correlated with the strain energy of the tetrahedral intermediate or the product. Systems having strained tetrahedral intermediates or products experience low rates and vice versa [ 51 , 52 , 54 , 91 ]. Acid-catalyzed hydrolysis of maleamic acids 34 - Atenolol is a relatively polar hydrophilic compound with water solubility of The net effect of atenolol on controlling both the heart rate and blood pressure is the reduction in myocardial work and oxygen requirement which reduces cardiovascular stress, thereby preventing arrhythmia and angina attacks.

Atenolol has a pKa of 9. Proposed mechanism for the acid-catalyzed hydrolysis of maleamic acids. Atenolol peak blood levels are reached within two to four hours after ingestion. Differently from propranolol or metoprolol, atenolol is resistant to metabolism by the liver and the absorbed dose is eliminated by renal excretion. The elimination half-life of atenolol is between 6 to 7 hours and there is no alteration of kinetic profile of a drug by chronic administration.

Atenolol is one of the most important medicines used for prevention of several types of arrhythmias in childhood, but unfortunately it is still unlicensed [ ].

Atenolol is available as 25, 50 and mg tablets for oral administration. However, most of these medicines are not formulated for easy or accurate administration to children for the migraine indication or in elderly patients who may have a difficulty swallowing tablets. Attempts to prepare a liquid formulation was challenging because atenolol is unstable in solutions. Atenolol syrup is stable only for 9 days. Furthermore, atenolol bitterness is considered as a great challenge to health sector when used among children and geriatrics [ ].

The main problem in oral administration of bitter drugs such as atenolol is incompliance by the patients [ 1 ] and this can be overcome by masking the bitterness of a drug either by decreasing its oral solubility on ingestion or eliminating the interaction of drug particles to taste buds [ 2 ]. Thus the development of bitterless and more lipophilic prodrug that is stable in aqueous medium is a significant challenge.

Improvement of atenolol pharmacokinetic absorption properties and hence its effectiveness may increase the absorption of the drug via a variety of administration routes. The aims of the study described in this section were: 1 design of atenolol prodrugs that can be i formulated in aqueous solutions and be stable over a long period of time, ii bitterless compounds having the capability to convert in physiological environment to the parent active drug, atenolol, in a controlled manner and 2 synthesis, characterization and in vitro kinetic study of the conversion of the designed prodrugs to their parent drug in different pHs physiological media.

The proposed atenolol prodrugs that were designed based on the acid-catalyzed hydrolysis reactions of N-alkyl maleamic acids Figure 5 are depicted in Figure 7. As shown in Figure 7 , the only difference exists between the proposed atenolol prodrugs and their parent drug is that the amine group of atenolol was replaced with an amide moiety.

Replacing the free amine in atenolol with an amide is expected to increase the stability of the prodrug thus formed due to general chemical stability for tertiary alcohols over amine alcohols.

In addition, recent stability studies on atenolol esters have demonstrated that the esters were more stable than their corresponding alcohol, atenolol, when formulating in aqueous solutions. Furthermore, kinetic study on atenolol and propranolol demonstrated that increasing the lipophilicity of the drug leads to an increase in the stability of its aqueous solutions.

For example, paracetamol 30 , a widely used pain killer found in the urine of patients who had taken phenacetin has a very unpleasant bitter taste. Phenacetin 31 , on the other hand, lacks or has very slight bitter taste.

The difference in the structural features of both drugs is only the group in the para position of the benzene ring. On the other hand, acetanilide 32 is a bitterless compound with a chemical structure similar to that of paracetamol and phenacetin but lacks the group in the para position of the benzene ring.

These facts suggest that the presence of the hydroxyl group on the para position of the benzene ring is the major contributor for the bitterness of paracetamol. It is likely that paracetamol bitterness is a result of interactions via hydrogen bonding of the phenolic group in paracetamol with the bitter taste receptors. The proposed atenolol prodrugs, atenolol ProD 1 and atenolol ProD 2 , have a hydroxyl and carboxylic acid groups hydrophilic moiety and the rest of the prodrug molecule is a lipophilic moiety Figure 7 , where the combination of both groups ensures a moderate hydrophilic lipophilic balance HLB.

It is worth noting that the HLB value of atenolol prodrug will be largely determined on the pH of the physiological environment by which the prodrug is exposed to. For example, in the stomach pH, the atenolol prodrugs, ProD 1 and ProD 2, will exist in the free carboxylic acid form whereas in the blood circulation the carboxylate form will be dominant. It was planned that atenolol ProD 1 - ProD 2 Figure 7 will be formulated as sodium salts since the carboxylate form is expected to be quite stable in neutral aqueous medium.

However, upon dissolution in the stomach pH less than 3 the proposed prodrugs will exist mainly as a carboxylic acid form thus enabling the acid-catalyzed hydrolysis to commence.

Acid-catalyzed hydrolysis for atemolol ProD 1 and atenolol ProD 2. The effective molarity EM parameter is a commonly tool used to predict the efficiency of intramolecular reactions when bringing two functional groups such as an electrophile and a nucleophile in a close proximity.

Intramolecularity is usually measured by the effective molarity parameter. Ring size, solvent and reaction type are the major factors affecting the EM value. Ring-closing reactions via intramolecular nucleophilic addition are much more efficient than intramolecular proton transfer reactions. EM values in the order of 10 9 13 M were determined for intramolecular processes occurring through nucleophilic addition. Whereas for proton transfer processes values of less than 10 M were measured for proton transfer processes until recently where values of 10 10 was documented by Kirby on the hydrolysis of some enzyme models [ 60 , 78 - 84 ].

For obtaining the EM values for processes 34 - 42 and atenolol ProD1 - 2 the kinetic and thermodynamic parameters for their corresponding intermolecular process, Inter Figure 8 were calculated.

Using equations 1 -4, equation 5 was derived, and describes the EM term as a function of the difference in the activation energies of the intra-and the corresponding inter-molecular processes. The calculated EM values for processes 34 - 42 and ProD 1 - 2 were calculated using equation 5.

Acid catalyzed hydrolysis for process Inter. The calculated EM values from eq. The correlation results demonstrate that processes 35 and 37 werethe most efficient among 34 - 38 , whereas process 4 was the least. The discrepancy in the rates of processes 35 and 38 on one hand and process 37 on the other hand is might be attributed to strain effects. Good correlation was obtained with R value of 0. Utilizing eq. Kinetics of the acid-catalyzed hydrolysis for atenolol ProD 1 was carried out in an aqueous buffer in a similar manner to that done by Kirby on N-alkylmaleamic acids 34 - This is in order to examine whether atenolol prodrug is hydrolyzed in aqueous medium and to what extent, suggesting its fate in the system.

Under the experimental conditions, atenolol ProD 1 was hydrolyzed to release the parent drug, atenolol, Figure 10 as was evident by HPLC measurements. At constant pH and temperature, the reaction displayed strict first order kinetics as the k obs was fairly constant and a straight line was obtained on plotting log concentration of residual atenolol prodrug verses time.

In addition, buffer pH 5 mimics the beginning of the small intestine environment. The medium at pH 7. On the other hand, at pH 7. Since the pK a of the carboxylic group of atenolol ProD1 is in the range of , it is expected at pH 5 the anionic form of the prodrug will be dominant and the percentage of the free acid form that expected to undergo hydrolysis will be relatively low. Thus, the difference in rates at the different pH buffers.

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 [ - ].

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. Key words: Bitter taste, taste buds, taste masking techniques. Introduction In earlier days it was believed that the drugs having bitter taste are more efficient as well as more curable. This concept has been reversed with development of numerous formulation techniques.

In recent era oral administration of bitter drugs with an acceptable degree of palatability becomes key issue for the health care providers, especially for pediatric and geriatric patients. Palatability is the combination of sensory perceptions including taste and smell and to a lesser extent texture, appearance and temperature of the products. The function of taste buds is to relay information about the taste of the molecule to the central nervous system. Each taste type affects the receptor cells through distinct mechanisms.

This complex cascade of bio chemical events results in taste cells sending a signal to the brain that is interpreted as bitter and unpleasant. Thus preventing interaction between active molecule and taste bud could mask bitter taste. Numbers of therapeutically active herbal molecules are having bitter taste. The unpleasant and unacceptable taste can be modified using below mentioned suitable techniques.

Since last two decades large numbers of industrially viable techniques, are very well explored for the taste masking of bitter drugs.

The present article gives an overview of past and current scenario of taste masking techniques. Taste buds are onion-shaped structures containing between 50 to taste cells. There they either interact with surface proteins known as taste receptors or with pore-like proteins called ion channels. These interactions cause electrical changes within the taste cells that trigger them to send chemical signals that translate into neurotransmission to the brain.

Salt and sour responses are of the ion channel type of responses, while sweet and bitter are surface protein responses. The electrical responses that send the signal to the brain are a result of a varying concentration of charged atoms or ions within the taste cell.

These cells normally have a net negative charge. Tastants alter this state by using varying means to increase the concentration of positive ions within the taste cell. This depolarization causes the taste cells to release neurotransmitters, prompting neurons connected to the taste cells to relay electrical messages to the brain.

In the case of bitter taste, such as quinine, stimuli act by binding to G-protein coupled receptors on the surface of the taste cell. This then prompts the protein subunits of alpha, beta, and gamma to split and activate a nearby enzyme. The signal now sent to the brain is interpreted as a bitter taste.

Based upon the recent theory that taste cells can interpret and process all the different stimuli, a method of diminishing the overall response to one stimulus would be to introduce a second stimulus. This is based upon the assumption that differences among responses to stimuli are not so much a distinction between firing and non-firing of the neurons, but instead the difference in the amount of firing.

This theory is the basis for the current research being presented in this paper: the ability to transform the responses of certain stimuli by introducing other stimuli. Effective blocking of the taste receptors can be accomplished by either coating the surface pore or competing within the channel themselves to reduce the net effect of the bitter stimuli firings.

While the introduction of competing stimuli is part of the masking system, specific flavours and sweetness profiles are essential to complete the experience and produce a pleasant taste for the consumer. During almost last three decades advanced novel formulation techniques have been utilized to improve the aesthetics of the final products.

The present review compiles the age old conventional methods as well as new techniques for taste masking. Conventional methods: Taste masking by amino acids, sweeteners, flavors and proteins This techniques is the most simple and very old technique for improving taste characteristics of active component of the formulations.

Taste masking can be achieved by using various amino acids like glycine, alalnine, leucine etc. Anticholesterolemic saponins containing foods, beverages along with pharmaceuticals are supplemented with amino acids for taste masking Protein like compositions, useful for improvement of liver disorders, severe burn, trauma etc. The taste of ampicillin improved markedly by preparing its granules with glycine and mixing them with additional quantity of glycine, sweeteners, flavours and finally compressing them into tablets 14, Sweeteners like sucrose and its derivatives, sodium saccharin, aspartame, stevoside, monosodium glycyrrhizinate and flavouring agents like lemon water, vanillin, citrus etc.

Starch and sorbitol as excipients with vanilla flavour, pork flavour and citrus flavour could be incorporated to mask the taste. Gelatin and flavouring agents mask bitter taste of tannic acid presumably by viscosity effect when made into a jelly by cooling A gelatine gum like formula containing tannic acid, gelatine, chocolate flavour and water masked taste of tannic acid.

Natural source based flavouring and perfuming agents are most widely used in pharmaceutical industry to mask the bitter taste of active component. The selection of flavouring agent should be complementary with sweetening agent and colouring agent in order to improve the aesthetics parameters to the formulations. The composition of such a formulation comprises a taste-masking liquid base with a high viscosity induced by thickening agents such as polyethylene glycol and sodium carboxy methylcellulose.

This type of formulations can incorporate higher amount of active ingredient then regular strength. Taste masking of chloroquine was masked using the same principal. Using glyceryl diester of C6- C22 fatty acid or diglycerine or sucrose fatty ester bitter taste of oral pharmaceuticals could be controlled.

An aqueous solution containing quinine sulphate with diglyceride from rapeseed oil and sucrose with ester did not taste bitter. Hence, any excipient, which can impart viscosity in mouth and coating of taste buds, can successfully used for taste masking.

Formulations with a large excess of lecithin or lecithin-like substances are claimed to control bitter taste in pharmaceuticals. Magnesium aluminum silicate with soybean lecithin is used to mask the unpleasant taste of talampicillin HCl. These agents cause numbness of taste buds and hence the sensory buds will not be able to recognize the bitter taste.

However, the time period for this numbness remains for 4 to 5 second. Fine powder of bees wax, sodium phenolate and active substance mixed with crosco vegetable oil, lime floss sugar and converted into lozenges. This formulation produced numbness of taste buds Formulations like mouthwashes or cough drops like eucalyptus oil can be masked by adding frenchone , isoborneol , borneol.

Potentiators increase the perception of the taste of sweeteners and mask the unpleasant taste. Various potentiators include thaumatine, neohesperidine dihydro chalcone NHDC and glycyrrhizin increase the perception of sodium or calcium saccharinates, saccharin, acesulfame, cyclamates etc. Most salts of organic compounds are formed by the addition or removal of proton to form an ionized drug molecule, which is then neutralized with a counter ion. Magnesium salt of aspirin is almost tasteless.

The unpleasant taste of water soluble Ibuprofen was masked by preparing alkaline metal bicarbonate salt of Ibuprofen Taste masking with effervescent formulations Effervescent formulation contains components that can produce effervescence, like sodium bicarbonate, due to liberation of carbon dioxide. Sodium bicarbonate reacts with the acid when the effervescent preparation is added to water. The solution remaining after effervescence is known as carbonated water.

The medicament dissolves in the carbonated water which serves to mask bitter, saline or nauseous taste of medicament. Studies carried out on effervescent granules of cetrizine showed better patient compliance 27 Taste masking by Prodrug formulation of the drug A prodrug is a chemically modified inert drug precursor that upon biotransformation liberates the pharmacologically active drug.

Prodrugs can be used to increase or decrease the aqueous solubility, mask bitterness, increase lipophilicity, improve absorption, decrease local side effects, and alter membrane permeability of the parent molecule 28 For example,.

Erythromycin estolate. In aqueous solution, erythromycin exists as protonated form which has solubility in water. Lauryl sufate salt of Erythromycin estolate, a prodrug, is water insoluble. It does not impart bitter taste when comes in contact with taste buds unlike parent drug The palmitate ester of chloramphenicol, a prodrug, used in pediatric suspension shows good patient IJPT July Vol. Some other examples include propoxyphen napsylate, tasteless and sparingly soluble derivative of Propoxyphen, clindamycin-2 palmitate, a prodrug of clindamycin.

Numbers of bitter drugs are formulated as coated dosage forms.