Presented by Sagar B. Thoke M. Pharm IInd Semester [Dept. of Pharmaceutics]Guided by

Prof . Y. P. Sharma S.N.D. College of Pharmacy, Babhulgaon.

ASeminar on

Taste Masking Methods in Pharmaceutical Formulations

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Introduction

Factors Affecting Selection of Taste Masking Technology

Factors Consideration During The Taste-Masking Formulation

Process

Ideal Characteristics of Taste Masking Process & Formulation

Taste Masking Approaches

Evaluation Techniques

Introduction

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Children, older persons-

Trouble swallowing tablets or capsules

Prefer liquid or sublingual/ Chewable solid

form dosage form

Undesirable taste-

Important formulation problems in case of Oral formulation

Patient compliance

Introduction

Need to Formulate Taste Masked Oral formulations.

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Vasculature Lingual artery Jugular vein

Nerve supply Facial nerve CN VII Glossopharyngeal nerve CN IX

Anatomy & Physiology of Tongue

Musculature Intrinsic Extrinsic

Taste buds (taste cells) Sense different tastes

Tongue physiology

Fig. Physiology of Taste Bud

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Four fundamental sensations of taste

Sweet and salty, mainly at the tip Sour, at the sides Bitter, at the back fifth is Umami (2002)

Fig. Taste Points in Tongue Taste Signaling Pathways

1. Drug (tastant) binds with G-PCR in the cells 2. triggering the release the release of G-Protein (Gustducin)

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Taste Blocking Mechanism

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Conventional taste masking techniques alone are often inadequate in masking the taste of highly bitter drugs such as quinine, celecoxib.

Coating imperfections, reduce the efficiency of the technique. Microencapsulation of potent bitter azithromycin is insufficient

to provide taste masking of liquid oral suspensions.

Factors Affecting Selection of Taste Masking Technology

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1. Extent of the bitter taste of the API & Required dose load.

2. Drug particulate shape and size distribution.

3. Drug solubility and ionic characteristics.

4. Required disintegration and dissolution rate of the finished

product.

5. Desired bioavailability & release profile.

6. Required dosage form.

Factors Consideration During The Taste-Masking Formulation Process

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Ideal Characteristics of Taste Masking Process & Formulation

1. Involve least number of equipments and processing steps.

2. Effectively mask taste with as few excipients which are economically and easily available.

3. No adverse effect on drug bioavailability.

4. Least manufacturing cost.

5. Can be carried out at room temperature.

6. Require excipients that have high margin of safety.

7. Rapid and easy to prepare.

It should

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Taste Masking Approaches

Two approaches are commonly utilized

1. By reducing the solubility of drug in the pH of saliva (5.6 - 6.8).

2. By altering the affinity and nature of drug which will . interact with the taste receptor.

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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%.

Fig. Geographical distribution of taste masking patents &

patent application filed in the period of year 1997 to 2007.

Taste Masking Technologies

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Fig. Taste masking technology filed in the period of

year 1997 to 2007.

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

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Natural Flavors-

Flavors

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

Synthetic Flavors-

Alcoholic solutions, aqueous solutions, Powders.

1. Taste Masking with Sweeteners and Flavor's

Sweeteners

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

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Natural Artificial Nutritive Non-

Nutritive

Polyols Novel

Sucrose,

Glucose,

Fructose,

Sorbitol,

Mannitol,

Honey,

Glycerol,

Liquorice

Saccharin,

Saccharin

Sodium,

Aspartame

Sucrose,

Fructose,

Glucose

Aspartam,

Sucralose,

Neotame,

Saccharine

Mannitol,

Sorbitol,

Xylitol,

Erythritol,

Maltitol

Trehalose,

Tagatose.

Sweeteners used for taste masking

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2. Polymer Coating of Drug

Coating acts as a physical barrier to the drug particles, by minimizing interaction between the drug and taste buds.

Powders (50 mm) is fluidized by heated, high-velocity air, and the drug particles are coated with a coating solution introduced from the top as a spray through a nozzle.

Nontoxic polymer that is insoluble at pH 7.4 and soluble at acidic pH are used.

chewable tablet of crystalline ibuprofen and methacrylic acid copolymer coating.Fig. Coating process

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3. Formation of Inclusion Complexes

Complexation of guest molecule with host form a stable complex.

1. Decreasing its oral solubility or

most suitable only for low dose drugs. β-CD cyclic oligosaccharide obtained from starch.

Fig. Scanning electron micrograph of uncoated (bitter) and coated (taste masked) paracetamol particles.

2. Decreasing the amount of drug particles exposed to taste buds.

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4. Ion Exchange Resin Complexes (IER)

Most drugs possess ionic sites in their molecule.

Classification Strong cation exchanger- sulphuric acid sites Weak cation exchanger- carboxylic acid moieties Strong anion exchanger- quaternary amine ionic sites Weak anion exchanger- predominantly tertiary amine

substituents

Drug-resin complex does not dissociate at salivary pH conditions.

Indion 204, 234, 244, 254; Tulsion T-335, T- 339, T-334; Amberlite IRC 50, IRP 69, IRP 88, IR 120; Dowex 50.

e.g.

IERs- high mole. weight polymers with cationic and anionic functional groups.

Not used- Amberlite IR400; Amberlite IR4B; Dowex 1; Indion 454; Duolite AP143.

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5. Solid Dispersion

One or more active ingredients Dispersed in an inert carrier or matrix at solid state.

Carriers used- povidone, PEG, HPMC, urea, mannitol and ethylcellulose.

Methods of Preparation Melting method Solvent method Melting solvent method

Dimenhydrinate with polyvinyl acetate phthalate solid dispersion .

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6. Microencapsulation

Thin coating to small particles of solids, droplets of liquids and dispersions.

Reduce its solubility in saliva & Act as physical barrier between drug and taste buds

Coating agents e.g.

• Gelatin, povidone, hydroxyethyl cellulose, ethyl cellulose, bees wax, carnuba wax acrylics and shellac. • water insoluble polymers- cellulose ethers, cellulose ester,

polyvinyl acetate and • water soluble polymers- cellulose acetate butyrate, PVP,

hydroxyethyl cellulose.

Clarithromycin with combination of gelatine and acrylic resins (Eudragit L-100, Eudragit S-100 & E-100).

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7. Multiple Emulsions

API entrapped in internal phase of w/o/w or o/w/o emulsion.

w/o/w or o/w/o emulsion of chloroquine phosphate.

8. Development of Liposome

Liposomes- simple microscopic vesicles in which aqueous volume (drug or biological agent) is entirely closed by a membrane composed of lipid molecules.

lipid bilayers mainly composed of natural or synthetic phospholipids.

e.g. phosphatidic acid, phosphatidylinositol, soy lecithin.

Chloroquine phosphate in HEPES (N-2-hydroxyetylpiperzine-N’- 2- ethane sulfonic acid) buffer was masked at pH 7.2. by incorporating into egg phosphatidyl choline.

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9. Prodrug Approach

Chemically modified inert drug precursor upon biotrans-formation liberates the pharmacologically active parent compound.

changing the molecular configuration of the parent molecule taste receptor‐substrate adsorption constant may be modified.

Increase or decrease the aqueous solubility, mask bitterness, increase lipophilicity, improve absorption, decrease local side effects, and alter membrane permeability of the parent molecule.

Parent Drug Prodrug

Erythromycin Erythromycin Propionate

Clindamycin Clindamycin palmitate ester

Chloramphenicol Chloramphenicol palmitate ester

Examples of Prodrugs with improved taste

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10. Taste Masking by Adsorption

Adsorbate of Drug are less saliva soluble versions of drugs.

Solution of the drug mix with an insoluble powder that will absorb the drug, removing the solvent, dry it.

Loperamide and phenyl propanolamine Suspension- adsorbed on magnesium aluminium silicates (Veegum F).

e.g. veegum, bentonite, silica gel and silicates.

11. Taste Masking with Lipophilic Vehicles like Lipids and Lecithins

Oils, surfactants, polyalcohols, and lipids effectively increase the viscosity in the mouth and coat the taste buds.

Talampicillin HCl- Magnesium aluminum silicate with soybean lecithin.

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12. Taste Suppressants and Potentiators

Suppressants (bitter taste blockers) compete with bitter substances to bind with the G-protein coupled (GPCR) receptor sites.

Bitter substances (hydrophobic) contributes greatly to their binding and inter-action with the receptor sites.

• Lipoproteins (phosphatidic acid and β-lactoglobulin) • adenosine monophosphate• Phospholipid (BMI-60) • hydroxyl flavanones & γ-aminobutanoic acid

Not affecting taste due to the sugars, amino acids, salts or acids.

Mixture of cooling (e.g. eucalyptol) and warming agents (e.g. methyl salicylate) was used for taste masking of thymol.

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Potentiators increase the perception of the taste of sweeteners.

• thaumatine, • neohesperidine dihydrochalcone (NHDC) and • glycyrrhizin

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

• phenols • sodium phenolates

Increase the perception of sodium or calcium saccharinates, saccharin, aspartyl-phenyl-alanine, cyclamates.

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13. Taste masking by gelation

Water insoluble gelation on the surface of tablet containing bitter drug .

Sodium alginate- form water insoluble gelation in presence of bivalentmetal ions.

In presence of saliva, sodium alginate react with bivalent calcium and form water insoluble gel and thus taste masking achieved

Amiprolose hydrochloride tablet undercoat of sodium alginate and overcoat of calcium gluconate.

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14. Formation of salt and derivative

Salt formation decreasing the solubility of drug (less soluble in saliva).

• N, N- dibenzyl ethylenediamine diacetate salts or • N, N bis (deyhdroabiety) ethylene diamine salts is tasteless.

Ibuprofen water-soluble salts using alkaline metal bicarbonate (sodium bicarbonate).

Aspirin tablets with magnesium salt of aspirin.

Sodium salts- sodium chloride, sodium acetate, sodium gluconate

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15. Use of Amino Acids and Protein Hydrolysates

Amino acids or their salts with bitter drugs.

• sarcosine, • alanine, • taurine, • glutamic acid, and • glycine.

Ampicillin taste improved by its granules with glycine and

additional quantity of glycine, sweeteners, flavors at final compression step.

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a) By effervescent agents

16. Miscellaneous

It comprises chewing gum base an orally administrable medicament Taste masking generator of carbon dioxide optionally a taste bud desensitizing composition e.g. oral

anaesthetics (benzocaine and spilanthol) and other non active material, (sweeteners, flavours, and fillers).

Fentanyl and prochlorperazine effervescent tablets for buccal, sublingual, and gingival absorption.

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b) Rheological modification

Rheological modifier (gums or carbohydrates)- lower the diffusion of bitter substances from the saliva.

For administration of liquid preparation.

High viscosity induced by thickening agents • PEG and • sodium CMC

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

Mirtazapine (antidepressant) aqueous suspension using methonine (stabilizer) and maltitol (thickening agent).

Terbutaline cough syrups given in doses of 4mg/5ml.

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c) Continuous multipurpose melt (CMT) technology

Continuous granulation and coating of API.

d) Wet Spherical Agglomeration (WSA)

Microencapsulation process combined with wet spherical agglomeration (WSA).

E.g. Enoxacin taste masking.

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e) Freeze Drying Process

Used to develop FDT.

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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Evaluation Techniques

Taste masking efficiency as

Asses by

in vivo and in vitro.

Quality control parameter and Determining the rate of release of drug from taste-masked

complex.

To quantitatively evaluate taste sensation, following methods have been reported

a. Human Panel testing (human subjects)b. Multichannel taste sensor/ magic tonguec. Spectrophotometric evaluation/ D30’s value

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In vivo Evaluation

a. Human Panel testing (human subjects)

5‐10 healthy volunteers with organoleptic sense.

Taste evaluation using reference solutions ranging from tasteless to very bitter.

Place the dosage form in mouth for 10 seconds.

Two sensory analysis methods used- Flavor Profile and Profile Attribute Analysis

Demands large panels and elaborate analysis. raises safety and scheduling issues. time consuming and expensive.

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Bitterness recorded against pure drug using a numerical scale.

seven point scale 1 = no bitterness, 2 = very slight bitterness, 3 = slight bitterness, 4 = slight to moderate bitterness, 5 = moderate bitterness, 6 = moderate to strong bitterness, and 7 = strong bitterness.

untrained taster would perceive an objectionable and/or noticeable bitterness if the bitterness score is greater than or equal to 3.

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In vitro Evaluation

automated taste sensing device to detect the magnitude of bitterness.

“E-Tongue” electronic sensor array technology 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).

b. Multichannel Taste Sensor / Magic tongue

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Seven (7) sensors designated by Alpha MOS ZZ, AB, BA, BB, CA, DA, and JE.

chemically modified sensors- field effect transistors (Chem FET), similar to an ion selective FET but are coated with a proprietary coating/membrane.

Ag/AgCl reference electrode

probes consist of a silicon transistor with proprietary organic coatings.

measurement done potentiometrically.

taste profile and statistical software interprets the sensor data into taste patterns.

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Reference electrode and sensors are dipped in a beaker containing a test solution for 120 seconds.

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Astree Electronic Tongue from Alpha MOS.wmv

Click 2 times on the below image

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c. Spectrophotometric Method

known quantity of formulation mixed with 10 ml of distilled water in 10 ml syringe by revolving the syringe, end to end; five times in 30 seconds.

filtered through a membrane filter & 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.

Sparfloxacin granules, with threshold concentration being 100μg/ml.

Generally the taste evaluation involves objective or analytical method and subjective or hedonic method

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Conclusion

Taste masking of bitter drugs has been a challenge to the

scientist. There are numbers of technologies available, which

effectively mask the objectionable taste of drugs. Selection of

technology depends upon the bitterness of drugs and their

compatibility with taste masking agents that does not affect the

bioavailability of drug. With application of these techniques and

proper evaluation of taste masking effect one can improve

product preference to a large extent. Moreover, the development

of taste masking methodology requires great technical skill, and

the need for massive experimentation.

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References

1) Gupta A. K., Practical Approaches for Taste Masking of Bitter Drug: A Review, International Journal of Drug Delivery Technology (April-June 2010), Vol. 2, Issue 2, Page no.- 56-61.

2) S. B. Ahire, A Review: Taste Masking Techniques in Pharmaceuticals, An International Journal of Pharmaceutical Sciences (2011), Page no.- 1645-1657.

3) Aditi Tripathi, Taste Masking: A Novel Approach for Bitter and Obnoxious Drugs, Journal of Pharmaceutical Science and Bioscientific research (Nov-Dec 2011), Vol. 1, Issue 3, Page no.- 136-142.

4) Vijay D. Wagh, Taste Masking Methods and Techniques in Oral Pharmaceuticals: Current Perspectives, Journal of Pharmacy Research (2009), Vol. 2, Issue 6, Page no.-1049-1054.

5) Vijay A. Agrawal, Taste Abatement Techniques to Inprove Palatability of Oral Pharmaceuticals: A Review, International Journal of Pharma Research and Development (Sep. 2010), Vol. 2, Issue 7, Page no.- 1-10.

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6) Vinod M. Sonawane, An Update of Taste Masking Methods and Evaluation Techniques, Scholars Research Library, Der Pharmacia Lettre (2010), Vol. 2, Issue 6, Page no.- 1-15.

7) Sidharth Puri, Taste Masking: A Novel Approch For Bitter And Obnoxious Drugs, International Journal of Biopharmaceutical & Toxicological Research (May 2011), Vol. 1, Issue 1, Page no.- 47-56.

8) J.K. Lorenz et al., Evaluation of a Taste Sensor Instrument (electronic tongue) for Use In Formulation Development, International Journal of Pharmaceutics (2009), Page no.- 65–72.

9) K Gowthamarajan, Taste-Masking Technologies for Bitter Drugs, General Article Resonance (December 2004), Page no.- 25-32.

10) Arvind K. Bansal, Trends in Pharmaceutical Taste Masking Technologies: A Patent Review, Recent Patents on Drug Delivery & Formulation (2009), 3, Page no.- 26-39.

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11) A. M. Suthar, Ion Exchange Resin As An Imposing Method For Taste Masking: a Review, An International Journal of Pharmaceutical Sciences (2010), Vol-1, Issue-2, Page no.- 6-11.

12) Sanjay Daharwal, Taste Masking Method for Bitter Drug and Tasteless Dispersible Tablet: An Overview, Page no.- 1-9.

13) Rajesh Agrawal, Cyclodextrins – A Review on Pharmaceutical Application for Drug Delivery, International Journal of Pharmaceutical Frontier Research (Jan-Mar 2012), Vol. 2, Issue 1, Page no.- 95-112.

14) K.P. Sampath Kumar, Taste Masked Suspension, www.thepharmajournal.com (2012), Vol. 1 No. 2, Page no.- 1-6.

15) S. T. Birhade, Preparation and Evaluation of Cyclodextrin Based Binary Systems for Taste Masking, International Journal of Pharmaceutical Sciences and Drug Research (2010), Vol. 2, Issue 3, Page no.- 199-203.

16) Inderbir SINGH, Scientific Review Ion Exchange Resins: Drug Delivery and Therapeutic Applications, FABAD J. Pharm. Sci. (2007), 32, Page no.- 91-100.

Thank You…!

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