Review On Taste Masking Approaches' & Evalution- Sagar BEATS

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A Seminar on Presented by Sagar B. Thoke M . Pharm II nd 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 :- 2 5/18/2012

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The human tongue :- Organ for taste, help in speech, swallowing . 3 5/18/2012 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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4 5/18/2012 Taste Chemical Salty Ions (ex: sodium) Sweet Sugars , ketones, aldehydes , some amino acid Sour Acidic compounds Bitter Not yet known, possible link to toxicity Umami (savory)* L-glutamate/glutamic acid Fifth taste bud type discovered in 2002. Fig. Physiology of Taste Bud Fig. Taste Points in Tongue

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5/18/2012 5 Taste Signaling Pathways Taste 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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5/18/2012 6 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. 7 5/18/2012 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 masking Coating- 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. 8 5/18/2012 Ideal taste masking process & formulation properties :-

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9 5/18/2012 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.

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

Geographical distribution of taste masking patents and patent 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% 10 5/18/2012

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Taste masking technology filed in the period of year 1997 to 2007. (% contribution of each different taste masking technologies Calculated.) 11 5/18/2012

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5/18/2012 12 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 :- 13 5/18/2012

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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 14 5/18/2012

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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 15 5/18/2012

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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 agents Salt 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. 16 5/18/2012 2. Sweetners Complement flavors associated with sweetness Soothing effect on the membranes of the throat

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17 5/18/2012 Natural Sweetener Artificial Sweetener Nutritive Sweeteners Polyols Novel Sweeteners Sucrose, Glucose, Fructose Sorbitol, Mannitol, Glycerol Honey, Liquorice Saccharin, Saccharin Sodium Aspartame 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=1 Aspartame 180-200 Sucralose 600 Acesulfame K 200 Neotame 7,000-13,000 Saccharin 300 18 5/18/2012 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’. 19 5/18/2012 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 A bility to exchange counter-ions within aqueous solutions surrounding them. small (1-2 mm diameter) beads with pores structure. 20 5/18/2012 Classification A. Cation Exchange Resin strong cation exchanger contains sulphuric acid sites Weak cation exchangers based on carboxylic acid moieties. B. Anion Exchange Resin strong anion exchange resins have quaternary amine ionic sites attached to the matrix, 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. 21 5/18/2012 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 Medicament Name Functionality Polymer backbone Amberlite TM IRP64 Weak acid COO - Crosslinked polyacrylic Dextromethorphan , Dimenhydrinate Amberlite TM IRP69 Strong acid SO 3- Styrene- Divinyl Benzene Ranitidine

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22 5/18/2012 Amberlite TM IRP88 Weak acid COO - Crosslinked polyacrylic Talampacillin-HCl, Paroxetine Indion 204 Weak acid COO - Crosslinked polyacrylic Norfloxacin, Ofloxacin Indion 214 Weak acid COO - Crosslinked Polyacrylic Azithromycin Indion 234 Weak acid COO - Crosslinked Polyacrylic Ciprofloxacin, Chloroquin phosphate Kyron T-104 Weak acid COO - Crosslinked polyacrylic Cefpodoxime, proxetil Kyron T-114 Weak acid COO - Crosslinked Polyacrylic Ofloxacin Kyron T-134 Weak acid COO - Crosslinked polyacrylic 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. 23 5/18/2012 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 acetate water 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. 24 5/18/2012 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. 25 5/18/2012 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. B y derivative formation, the geometry is altered, affecting the adsorption constant. 26 5/18/2012 changing the molecular configuration of the parent molecule change Magnitude of a bitter taste. N albuphine HCL, naltrexone, naloxone, oxymorphone HCL, butorphanonol, and levallorphan tasteless prodrug for buccal administration.

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27 5/18/2012 Parent Drug Prodrug Erythromyci Erythromycin Propionate Clindamycin Clindamycin palmitate ester Chloramphenicol Chloramphenicol palmitate ester Morphine N-oxide derivatives of all Morphine Triamcinolone 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. H ydrophobic 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) 28 5/18/2012 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 ). 29 5/18/2012 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. 30 5/18/2012 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. 31 5/18/2012 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 . 32 5/18/2012 Sensory evaluation It is possible to accurately and reproducibly measures taste thresholds. To quantitatively evaluate taste sensation, following methods used Panel testing (human subjects) Measurement of frog taste nerve responses. Multichannel taste sensor/ magic tongue Spectrophotometric evaluation/ D30’s value

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1] Panel Testing 33 5/18/2012 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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34 5/18/2012 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. 35 5/18/2012 In vitro Evaluation “E-Tongue” automated taste sensing device- detect magnitude of bitterness. O vercomes 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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P robes consist of a silicon transistor with proprietary organic coatings, which govern the probe’s sensitivity and selectivity, and measurement done potentiometrically . 36 5/18/2012 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 37 5/18/2012

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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. 38 5/18/2012

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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 , I on E xchange R esin As A n Imposing M ethod F or T aste M asking: 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. 39 5/18/2012

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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. P atidar ashish , A Review O n- R ecent A dvancement I n T he D evelopment of Rapid D isintegrating T ablet, 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. 40 5/18/2012

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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 R eview: Taste Masking T echniques in Pharmaceuticals, An I nternational J ournal of Pharmaceutical S ciences, IC Value – 4.01, Page no.- 1645-1657. Vijay A. Agrawal , T aste A batement T echniques to Inprove P alatability of Oral Pharmaceuticals: a Review, International Journal of Pharma Research and Development, 2010/VOV-2/ISSUE-7/SEP/008, Page no.- 1-7. 41 5/18/2012

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Thank you… T H A N K Y O U 42 5/18/2012