Review on Taste msking Approches & Evalution

ASeminar on

Presented by

Sagar B. Thoke M. Pharm IInd Semester

[Dept. of Pharmaceutics]Guided by

Prof . Y. P. Sharma

Review On: Taste Masking Approaches' & Evalution.

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The human tongue- Anatomy & Physiology

Problems arise in taste masking

Ideal taste masking process and formulation properties

Factors consideration during the taste masking

Approaches to Unpleasant Taste Inhibition

Evaluation of Taste Masking Effect

References

Contents :-

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The human tongue :- Organ for taste, help in speech, swallowing.

Anatomy & Physiology of the Tongue :-Tongue Muscles

Vasculature

receives blood supply primarily from the lingual artery, which drain into internal jugular vein.

Length-from the oropharynx to the tip is 10 cm (4 in).

Intrinsic muscles Extrinsic muscles

Tongue physiology

The chemicals bind their particular receptors and initiate signaling that travels through the nerves to the brain, where they are interpreted.

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Taste ChemicalSalty Ions (ex: sodium)Sweet Sugars, ketones, aldehydes, some amino acidSour Acidic compoundsBitter Not yet known, possible link to toxicity

Umami (savory)* L-glutamate/glutamic acid

Fifth taste bud type discovered in 2002.

Fig. Physiology of Taste BudFig. Taste Points in Tongue

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Taste Signaling PathwaysTaste transduction begins with the interaction of a tastant (eg. medicine or food) with taste receptor cells in the taste buds8 (Fig ). The tastant binds with G-Protein coupled receptors (GPCRS) in the cells triggering the release the release of G-Protein called Gustducin.

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Taste sensation begins when Gustducin activates the effector enzymes phosphodiesterase IA (PDE) or phospholipase C beta-2(PLC). The effector enzyme then changes the intracellular level of second messenger such as cyclic adenosine monophosphate (cAMP), Inositol, 1, 4, 5- triphosphate (IP3) and diacylglycerol (DAG). The second messengers activate calcium ion channel inside the cell and sodium, potassium and calcium channel on extra cellular membrane. Ionization depolarizes the cell causing release of neurotransmitters that send nerve impulses to the brain that carries the signal of bitter taste and taste blockers work by interfering with taste transduction.

Taste Blocking Mechanism

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Taste refers to a perception arising from the stimulation of taste buds.

Undesirable taste- problems in formulation & patient compliance.

Children, older persons, trouble swallowing tablets or capsules.

chewable solid form (sublingual or buccal tablets), liquid form or ODT.

Taste of Ciprofloxacin mask by sodium saccharin in ODT.

Taste masking- reduction of an undesirable taste.

Problems arise in taste masking :- Inadequate taste maskingCoating- imperfections, if present, reduce the efficiency.

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1) Involve least number of equipment's and processing steps.

2) Require minimum number of excipients for an optimum

formulation.

3) No adverse effect on drug bioavailability.

4) Least manufacturing cost.

5) Can be carried out at room temperature.

6) Require excipients that are economical, easily available with

high margin of safety.

7) Rapid and easy to prepare.

Ideal taste masking process & formulation properties :-

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Factors consideration during the taste masking :-

1) Extent of the bitter taste of the API.

2) Required dose load.

3) Drug particulate shape and size distribution.

4) Drug solubility and ionic characteristics.

5) Required disintegration & dissolution rate of finished

product.

6) Desired bioavailability.

7) Desired release profile.

8) Required dosage form.

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Geographical distribution of taste masking patents andpatent application filed in the period of year 1997 to 2007.

Taste masking patents and patent applications are contributed from

Asia-49.34%

North America- 41.45% of which 62.67% were filed in USA and

Europe- 9.30%

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Taste masking technology filed in the period of year 1997to 2007.

(% contribution of each different taste masking technologies Calculated.)

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Fig. Taste Masking Technologies uses in liquid and solid dosage forms

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1. Taste masking with flavors, sweeteners, and amino acids

2. Taste Masking by Inclusion Complexation

3. Taste Masking by Ion-Exchange Resins (IERs)

4. Taste Masking by Microencapsulation

5. Solid dispersion

6. Mass extrusions

7. Multiple Emulsions

8. Wax Embedding of Drug

9. Development of Liposome

10. Taste masking by adsorption

11.Taste masking by Prodrug approach

Approaches to Unpleasant Taste Inhibition :-

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12. Taste Masking with Lipophilic Vehicles like lipids and

lecithins

13. Taste Suppressants and Potentiators

14. Granulation

15. pH Modifiers

16. Freeze Drying Process

17. Viscosity Modifications

18. Salt Preparation

19. Taste masking by gelation

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1. Taste Masking with Sweeteners and Flavours

1. Flavors

Natural Flavors Synthetic Flavors

Natural Vs Synthetic

Cheaper More readily available Less variable in chemical composition More stable

Juices - Raspberry Extracts - Liquorices Spirits - Lemon & Orange Syrups – Blackcurrant Tinctures -Ginger Aromatic waters - Anise & Cinnamon Aromatic Oils – Peppermint & Lemon.

Alcoholic solutions Aqueous solutions Powders

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Flavoring agents for taste masking

Basis of Choosing a Flavor

Complementary to existing flavor of the drug Known popularity of particular flavors Age of patients Allergy

Basic Taste Masking agentsSalt Butterscotch, maple, apricot, peach, vanilla,

wintergreen mint.

Bitter Wild cherry, walnut, chocolate, mint, anise.Sweet Vanilla, fruit and berry.Sour Citrus flavor, licorice, root beer, raspberry.

2. Sweetners

Complement flavors associated with sweetness Soothing effect on the membranes of the throat

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Natural Sweetener

Artificial Sweetener

Nutritive Sweeteners

Polyols Novel Sweeteners

Sucrose,Glucose, FructoseSorbitol, Mannitol, GlycerolHoney, Liquorice

Saccharin, Saccharin SodiumAspartame

Sucrose, Fructose and Glucose

Mannitol, Sorbitol, Xylitol, Erythritol, Maltitol.

Trehalose, Tagatose

Taste masking of water soluble bitter drugs, with a high dose, is difficult to achieve by using sweeteners alone.

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List of FDA approved Non-Nutritive sweeteners

Sweeteners Sweetness factor, Sucrose=1Aspartame 180-200Sucralose 600

Acesulfame K 200Neotame 7,000-13,000

Saccharin 300

3. Amino Acids and Protein Hydrolysates

combining amino acids or their salts with bitter drugs, reduce the bitterness.

Amino acids- sarcosine, alanine, taurine, glutamic acid, and glycine.

Ampicillin granules with glycine and mixing them with additional quantity of glycine, sweeteners, flavors.

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2. Taste Masking by Inclusion Complexation

Drug molecule fits into the cavity of a complexing agent, i.e. the host molecule, forming a stable complex.

Vander Walls forces are mainly involved in inclusion complexes.

low stability constant lead to a rapid release of free drug

Hydrophobic drugs form complex by replacing ‘inclusion water’ while easily migrating (hydrophilic, well soluble) drugs form complex, assuming replacement of ‘crystal water’.

β-cyclodextrin- sweet, non-toxic, cyclic oligosaccharide obtained from starch.

Decreasing its oral solubility on ingestion or Decreasing the amount of drug particles exposed to taste

buds

Suitable only for low dose drugs.

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3. Taste Masking by Ion-Exchange Resins (IERs)

High molecular weight polymers With cationic and anionic

functional groups

Ability to exchange counter-ions within aqueous solutions

surrounding them.

small (1-2 mm diameter) beads with pores structure.

Classification

A. Cation Exchange Resina) strong cation exchanger contains sulphuric acid sites b) Weak cation exchangers based on carboxylic acid moieties.

B. Anion Exchange Resina) strong anion exchange resins have quaternary amine ionic sites

attached to the matrix, b) weak anion exchanger has predominantly tertiary amine

substituents.

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Drugs are attached to the oppositely charged resin substrate, by weak ionic bonding form insoluble complex.

which does not dissociates the drug-resin complex at salivary pH conditions.

Drug release depends on- properties of the resin and the ionic environment within the GIT.

Cation exchange or weak anion exchange resins

examples of IER – drug complex

Resin MedicamentName Functionality Polymer backbone  

AmberliteTM

IRP64Weak acidCOO-

Crosslinkedpolyacrylic

Dextromethorphan,Dimenhydrinate

AmberliteTM

IRP69Strong acidSO3-

Styrene-Divinyl Benzene

Ranitidine

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AmberliteTM

IRP88Weak acidCOO-

Crosslinkedpolyacrylic

Talampacillin-HCl, Paroxetine

Indion 204 Weak acidCOO-

Crosslinkedpolyacrylic

Norfloxacin, Ofloxacin

Indion 214 Weak acidCOO-

CrosslinkedPolyacrylic

Azithromycin

Indion 234 Weak acidCOO-

CrosslinkedPolyacrylic

Ciprofloxacin, Chloroquin phosphate

Kyron T-104 Weak acidCOO-

Crosslinkedpolyacrylic

Cefpodoxime, proxetil

Kyron T-114 Weak acidCOO-

CrosslinkedPolyacrylic

Ofloxacin

Kyron T-134 Weak acidCOO-

Crosslinkedpolyacrylic

Metronidazole

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4. Taste Masking by Microencapsulation

process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a film or polymeric material.

Coating created a physical barrier between the drug and the taste buds. Reduce its solubility in saliva and thus mask taste.

Factors to be consider

completely mask the taste of a bitter drug, & not adversely affecting the intended drug release profile.

Polymers used for coating-

water insoluble polymers- cellulose ethers, cellulose ester, polyvinyl acetatewater soluble polymers- cellulose acetate butyrate, PVP, hydroxyethyl cellulose

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5. Solid Dispersions

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.

Amine or amido group of dimenhydrinate can have a physical and chemical interaction with the carboxylic acid and esters groups.

Natural copolymers- shellac, zein and cellulose acetate phthalate hydrophobic polymers and long chain fatty acids.

enteric polymers like derivatives of acrylic acid polymers and phthalate are good choices

requires a higher concentration of excipients compared to other techniques

7. Multiple Emulsions

Bitter taste of chloroquine was masked in o/w/o and w/o/w emulsion system.

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9. Development of Liposome

Masking the unpleasant taste of therapeutic agent by entraping them into liposome.

Incorporation of drug into liposomes prepared with egg phosphatidyl choline masked the bitter taste of antimalarial, Chloroquine phosphate in HEPES (N-2- hydroxyethylpiperzine-N'-2 ethane sulfonic acid) buffer at pH 7.2.

10. Taste masking by adsorption

Adsorbate of bitter tasting drug less saliva soluble.

Preparing a solution of the drug and mix with an insoluble powder that will adsorb the drug, remove the solvent, dry it.

Veegum, bentonite, silica gel and silicates used as adsorbate.

Ranitidine with a synthetic cation exchange resin adsprbate.

Loperamide and phenyl propanolamine adsorbed on magnesium aluminium silicates (Veegum F) form taste masked suspension.

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11. Taste masking by Prodrug approach

Prodrug - chemically modified inert drug precursor which upon biotransformation liberates pharmacologically active parent compound.

reducing solubility, and thereby improving taste.

Bitterness of a molecule due to the efficiency of taste receptor substrate adsorption reaction, which is related to the molecular geometry of the substrate.

By derivative formation, the geometry is altered, affecting the adsorption constant.

changing the molecular configuration of the parent molecule change Magnitude of a bitter taste.

Nalbuphine HCL, naltrexone, naloxone, oxymorphone HCL, butorphanonol, and levallorphan tasteless prodrug for buccal administration.

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Parent Drug ProdrugErythromyci Erythromycin PropionateClindamycin Clindamycin palmitate esterChloramphenicol Chloramphenicol palmitate esterMorphine N-oxide derivatives of all MorphineTriamcinolone Triamcinolone diacetate ester

18. Salt Preparation

Adding alkaline metal bicarbonate (sodium bicarbonate) masks the unpleasant taste of water -soluble ibuprofen salts in aqueous solution.

Penicillin prepared as N, N-di benzyl ethylene diaminediacetate salts or N, N-bis (deyhdroabiety) ethylene diamine salts is tasteless.

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13. Taste Suppressants and Potentiators

Linguagen’s bitter blockers (e.g. adenosine monophos-phate) compete with bitter substances to bind with the G-protein coupled(GPCR) receptor sites.

Hydrophobic nature of drug contributes to binding and inter-action with the receptor sites.

lipoproteins composed of phosphatidic acid and β-lactoglobulin inhibit the taste nerve responses to the only bitter substances.

Lipoproteins are universal bitter taste blockers.

Phospholipid (BMI-60)

Suppressants

Neohesperidine phospholipids- interact chemically with the taste receptors.

Cooling and warming agents- extreme sensations to overpower the bitter taste and confuse the brain.

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Thymol taste mask by mixture of cooling (e.g. eucalyptol) and warming agents (e.g. methyl salicylate).

Potentiators- increase the perception of the taste of sweeteners.

Potentiators Sweeteners

Thaumatine, neohesperidine dihydrochalcone (NHDC) and glycyrrhizin

sodium or calcium saccharinates, saccharin, aspartyl-pheny-lalanine, acesulfame, cyclamates, and stevioside.

Bromhexine- Thaumatine with sugar alcohols mask taste.

Bitter taste blockers- Hydroxy flavanones, adenosine monophosphate and γ-amino butanoic acid.

Desensitizing agents- desensitize the taste buds by interfering with taste transduction.

e.g. phenols, sodium phenolates

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The enteric polymers (eudragit L) solubilize at pH beyond pH 5.5 & pH of saliva 5.8. possibility of drug partially leached.

15. pH Modifiers

pH Modifying agents- generating a specific pH microenvironment & facilitate in situ precipitation of bitter drug in saliva, reducing taste sensation.

L-arginine maintains alkaline pH of the vehicle to promote precipitation of des-quinolone in saliva.

16. Freeze Drying Process

Zydis and Lyoc technology- drug is physically entrapped in matrix composed of saccharide e.g. mannitol and a polymer

piroxicam, loperamide, ondansetron, chlorpheniramine are various drugs taste-masked by Zydis technology.

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Acetaminophen suspension with xanthan gum (0.1‐0.2%) and microcrystalline cellulose (0.6‐1%).

Gelatine and flavours (chocolate flavour) mask the bitter taste of tannic acid by viscosity effects, form jelly on cooling.

thickening agents such as PEG and NaCMC.

decrease contact between bitter drugs and the taste receptors.

Increasing viscosity with gums or carbohydrates can lower the diffusion of drug.

17. Viscosity Modifications

8. Wax Embedding of Drug

Tastes masked by embedded granules of ephedrine HCl, Chlorpheniramine maleate, Diphenhydramine HCl were prepared in stearic acid & other waxes.

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tedious work as the taste sensation varies person to person.

Evaluation of Taste Masking Effect

coated microsphere & Ion exchange resin- drug release rate can serve as an index of the degree of masking achieved.

Sensory evaluationIt is possible to accurately and reproducibly measures taste thresholds.

To quantitatively evaluate taste sensation, following methods used

1. Panel testing (human subjects)2. Measurement of frog taste nerve responses.3. Multichannel taste sensor/ magic tongue4. Spectrophotometric evaluation/ D30’s value

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1] Panel Testing

Numerical values are then assigned to these levels of bitterness (eg.,0‐5).

In vivo Evaluation The panel testing is a psychophysical rating of the gustatory

stimuli. 5‐10 human volunteers with organoleptic sense. reference solutions ranging in taste from tasteless to very

bitter. Normal dose was held in mouth for 60 seconds. Bitterness recorded against pure drug (test solution) is tasted

and rated on the same numerical scale to assess its bitterness.

0 = pleasant, 1 = Tasteless, 2 = No bitter but after taste give bitterness, 3 = immediately gives bitterness, 4 = slightly bitter, 5 = extremely bitter.

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Demands large panels and elaborate analysis, raises safety and scheduling issues and

Time consuming and expensive.

2] Measurement of Frog Taste Nerve Responses

Adult bull frogs glossopharyngeal nerve is located and dissected from the surrounding tissue and cut proximally

An ac‐amplifier and an electronic integrator used to amplify and integrate the nerve impulses.

The peak height of the integrated response is then taken as the magnitude of response.

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3] Multichannel Taste Sensor / Magic tongue

Transducers composed lipid/polymer membranes to detect taste as like to human gustatory sensation.

In vitro Evaluation

“E-Tongue” automated taste sensing device- detect magnitude of bitterness. Overcomes problems of panel testing.

recognition, quantitative multicomponent analysis and artificial assessment of taste and flavour.

It recognizes three levels of biological taste including 1] Receptor level (Taste buds in humans, probe membranes in E-Tongue), 2] circuit level (neural transmission in humans, transducer in E-Tongue), and 3] perceptual level (cognition in the thalamus humans, computer and statistical analysis in the E-Tongue).

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Probes consist of a silicon transistor with proprietary organic coatings, which govern the probe’s sensitivity and selectivity, and measurement done potentiometrically.

e.g. Quantification of Suppression of bitterness of Quinine by sucrose.

statistical software interprets the sensor data into taste patterns.

Liquid samples directly analysed, solids require to dissolve.

Reference electrode and sensors are dipped in a beaker containing a test solution for 120 seconds (as shown in fig.).

A potentiometric difference between each sensor and a reference electrode measured and analyzed by software.

E-Tongue enables us to test taste accurately without the need for human volunteers at earlier stages.

E-Tongue lose its sense of taste after long periods of testing

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Fig. : Evaluation of taste using e-tongue

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4] Spectrophotometric Method

A known quantity of the taste‐masked formulation is mixed with 10 ml of distilled water in 10 ml syringe by revolving the syringe, end to end, five times in 30 seconds.

test medium then filtered through a membrane filter, followed by spectrophotometric determination of the concentration of the drug in the filtrate.

If this concentration is below the threshold concentration, it

may be concluded that the bitter taste would be masked in vivo. This technique has been applied to evalute the taste masked

granules of sparfloxacin, with threshold concentration being 100μg/ml.

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References K.P. Sampath Kumar, THE PHARMA INNOVATION-Taste Masked

Suspension, www.thepharmajournal.com, Vol. 1 No. 2 (2012), Page no.- 1-6.

Nilesh Jain, Effect of superdisintegrants on formulation of taste masked fast

disintegrating Ciprofloxacin tablets, International Current Pharmaceutical

Journal 2012, 1(4): Page no.- 62-67.

Velmurugan S, Oral Disintegrating Tablets: An Overview, International

Journal of Chemical and Pharmaceutical Sciences 2010, Dec., Vol.1 (2): Page

no.- 1-10.

A. M. Suthar, Ion Exchange Resin As An Imposing Method For Taste

Masking: a Review, An International Journal of Pharmaceutical Sciences,

Vol-1, Issue-2, (2010), Page no.- 6-10.

Aditi Tripathi, Taste Masking: A Novel Approach for Bitter and Obnoxious

Drugs, Journal of Pharmaceutical Science Bioscientific Research, Volume 1,

Issue 3: Nov -Dec 2011 Page no.- 136-142.

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Zelalem Ayenew, Trends in Pharmaceutical Taste Masking Technologies: A

Patent Review, Recent Patents on Drug Delivery & Formulation 2009, 3, Page

no.- 26-39.

S. T. Birhade, Preparation and Evaluation of Cyclodextrin Based Binary Systems

for Taste Masking, International Journal of Pharmaceutical Sciences and Drug

Research 2010; 2(3): Page no.- 199-203.

Patidar ashish, A Review On- Recent Advancement In The Development of

Rapid Disintegrating Tablet, International Journal of Life science & Pharma

Research, Vol 1/Issue 1/Oct-Dec 2011, Page no.- 7-15.

Rajesh Agrawal, Cyclodextrins – A Review on Pharmaceutical Application for

Drug Delivery, International Journal of Pharmaceutical Frontier Research, Jan-

Mar 2012; 2(1), Page no.- 95-112.

Vijay D. Wagh, Taste Masking Methods and Techniques in Oral

Pharmaceuticals: Current Perspectives, Journal of Pharmacy Research 2009, 2(6),

Page no.- 1049-1054.

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Gupta A. K., Practical Approaches for Taste Masking of Bitter Drug: A Review,

International Journal of Drug Delivery Technology, 2010; 2(2), Page no.- 56-61.

S. B. Ahire, A Review: Taste Masking Techniques in Pharmaceuticals, An

International Journal of Pharmaceutical Sciences, IC Value – 4.01, Page no.-

1645-1657.

Vijay A. Agrawal, Taste Abatement Techniques to Inprove Palatability of Oral

Pharmaceuticals: a Review, International Journal of Pharma Research and

Development, 2010/VOV-2/ISSUE-7/SEP/008, Page no.- 1-7.

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