Taste Masking Of Pharmaceuticals

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Varsha Pokharkar

Taste is an important factor in the development of dosage form. Nevertheless it is that arena of product development that has been overlooked and undermined for its importance. Taste masking technologies offer a great scope for invention and patents.

The present review attempts to give a brief account of different technologies of taste masking with respect to dosage form and novel methods of evaluation of taste masking effect.

Introduction


Taste, smell, texture and after taste are important factors in the development of dosage forms. These are important factor in product preference. Good flavor and texture are found to significantly affect sell of the product. Undesirable taste is one of the important formulation problems encountered with most of the drugs. The methods most commonly involved for achieving taste masking include various chemical and physical methods that prevent the drug substance from interaction with taste buds. The simplest method involves use of flavor enhancers. Where these methods fail more complex methodologies are adopted. Various techniques have been identified for taste masking which include polymer coating, inclusion complex formation with cyclodextrin, use of ion exchange resins, solubility limiting methods, liposome, multiple emulsions, use of anesthetic agents, etc. The present review attempts to give a brief account of different technologies of taste masking with respect to dosage form along with novel methods of evaluation of taste masking effect.


Techniques Employed for Taste Masking


The methods commonly employed for achieving effective taste masking include various physical and chemical methods that prevent the drug substance from interaction with the taste buds. 


A) Use of flavor enhancers:


The materials for taste masking purpose have often been classified depending upon the basic taste that is masked1 (Table 1). Flavoring and perfuming agents can be obtained from either natural or synthetic sources.  Natural products include fruit juices, aromatic oils such as peppermint and lemon oils, herbs, spices and distilled fractions of these.  They are available as concentrated extracts, alcoholic or aqueous solutions, syrups or spirit2. Apart from these conventional materials many compositions have been found to show effective taste masking abilities with improved flavor such as alkaline earth oxide, alkaline earth hydroxide or an alkaline hydroxide3. Another composition includes phosphorylated amino acid such as phosphotyrosine, phosphoserine, and phosphothreonine and mixtures thereof4. Anethole effectively masked bitter taste as well as the aftertaste of zinc, which is use in treating the common cold5. Clove oil and calcium carbonate, which has been found to be particularly useful to mask the unpalatable active in formulations which are intended to be chewed or  dissolve in mouth prior to ingestion in solution6.


B) Applying polymer coatings:


Coating of drugs using a suitable polymer offer an excellent method of concealing the drug from the taste buds. The coated composition may be incorporated into much number of pharmaceutical formulations, including chewable tablet, effervescent tablets, powder, and liquid dispersion7, 8, 9.


Cuna et al.10 prepared microencapsules of cefuroxime axetil with various cellulosic polymers having a pH dependent solubility; CAT, BPMCP-55 and UPMCP-50, with the final aim to mask its taste while assuring its release in the intestinal cavity. The drug release studies and the stability assay of the encapsulated moiety demonstrated that UPMCP-55 microspheres represent a useful approach to achieve the proposed objectives.


Kato et al.11 studied the low melting point substances for masking bitter taste of the drug. Beef tallow (a low melting point substance) was mixed with micropulverized active ingredients (e.g. antiulcer methyl benactyzuim bromide) and the mixture was nozzle sprayed to form coated spheres having homogenous particle size.


Maccari et al.12 conducted a special study to assess the bioavailability of a Flucoxacillin preparation microencapsulated for taste abatement with 17 % ethyl cellulose made up as a granular’ product for extemporaneous resuspension when compared to commercially available Flucoxacillin preparations. Both dosage forms were bioequivalent proving that Flucoxacillin microencapsulated for taste abatement is as available from the dosage form as the raw unprocessed antibiotics.


Yajima et al.13 developed a method of taste masking using a spray congealing technique.  The spray congealing technique, which uses a spray dryer, is an effective method of taste masking because this method is cost effective and requires no solvent and it can produce a more dense film than other methods without moving materials for drying.  Also since this method is easy to industrialize and many attempts using this technique have been undertaken. They reported spherical matrices containing Clarithromycin (a macrolide antibiotic), amino alkyl-methacrylate, polymer-E (AMCE) and glyceryl monosterate as the ingredients, the objective being prevention of drug release in the mouth while ensuring rapid release in GIT.


Hiroya Sugao et al.14 prepared microparticles of Imdeloxazine (a bitter tasting drug) and coated them with a mixture comprising of hydrogenated oil and surfactants in a fluidized bed using side spray method.  Drug release from the coated particles was significantly delayed which was overcome by heat treatment.


Udea et al.15 described a novel microencapsulation process combined with the wet spherical agglomeration technique by using modified phase separation method in order to mask the bitter taste of drugs.


Yekta Ozer and Atilla Hincal 16 microencapsulated Beclamide in order to mask the bitter taste by a simple co-aservation method-using gelatin.


Multiple encapsulated flavor delivery systems has been developed which is useful in chewing gum, pharmaceuticals preparations as well as other food products.17


C) Complexation with ion exchange resins:


The adsorption of bitter drugs onto synthetic ion exchange resins to achieve taste coverage has been well documented. Borodkin et al.18 prepared high potency adsorbates of methapyrilene, dextromethorphan, ephedrine, pseudoephedrine by column procedures using a polymethacrylic acid ion exchange resin. Taste evaluation of the adsorbates showed a significant reduction in the bitterness of the drugs. Coating the adsorbate particles with 4:1 ethyl cellulose - HPMC mixture reduced the bitterness further. Taste coverage was maintained after incorporation of the coated adsorbate into chewable tablets. Strong acid cation resins (sulfonated stynedivinylbenzene copolymer product) can be used for masking the taste of basic drugs19. Polystyrene matrix cation exchange resins have been used to mask the bitter taste of chlorpheniramine maleate, ephedrine hydrochloride, and diphenhydramine hydrochloride20. Extreme bitterness of quinolones has been achieved by ion exchange resin such as methacrylic acid polymer cross linked with divinylbenzene21.


D) Inclusion complex formation with cyclodextrins:


Cyclodextrin is the most widely used complexing agent for inclusion complex formation which is capable of masking the bitter taste of the drug either by decreasing its solubility on digestion or decreasing the amount of drug particles exposed to taste buds there by reducing its perception of bitter taste. Bitter taste of ibuprofen and gymnima sylvestre has been effectively masked by cyclodextrin22, 23.


E) Other techniques:


These include solubility-limiting methods, incorporation of drugs in vesicles and liposome, and chemical modification24, 25. The solubility limiting method can be applied to a number of drugs whose taste profiles are dependent on aqueous solubility.


            Chemical modification such as derivatization or lipophillic counter ion selection may be an effective method for reducing aqueous solubility and taste Erythromycin monohydrate, a bitter tasting drug  with a solubility of 2 mg/ml is chemically converted into erythromycin ethyl succinate, the aqueous solubility is reduced to the < 50 mcg/ml. This form is tasteless and can be administered as a chewable tablet. Incorporation of drugs into vesicles or liposomes is although an ideal technique, yet a challenge to formulate without altering the regulatory status of the product (in vitro dissolution kinetics, physical or chemical stability or bioavailability)24.


Anesthetizing agent like sodium phenolate, which numb the taste buds sufficiently within 4-5 seconds is helpful in inhibiting the perception of bitter taste of the formulation26. Substances like lipids, carbohydrate, lecithin, gelatin and polyamines has been effectively used for taste masking of drugs27.


Another novel technique employing multiple emulsions has also been reported.  By dissolving drug in the inner aqueous phase of w/o/w emulsion under condition of good shelf stability, the formulation is designed to release drug through oil phase in the presence of gastric fluid28.


In one of the method drugs with bitter taste are combined with nonionic surfactants to form composites by hydrophobic interactions resulting in taste masking29.


Yoshimi et al.30 studied influence of heat treatment on dissolution and masking degree of bitter taste for novel fine granule system. It was suggested that heat treatment cause change of film properties such as tensile strength and wettability which is attributable to the melting and diffusing of sucrose fatty acid ester in the film resulting in the dissolution level being increased leads to the improvement in bitter taste30.


 


Techniques Employed for Taste Masking of Different Dosage Forms


The drug i.e. the active pharmaceutical ingredient is finally formulated in a suitable dosage form such as tablet, powder, liquid, etc.


I) Tablets:


Most of the tablets can be effectively masked for their taste by applying inert polymer coatings that prevent the interaction of the drug substance with the taste buds. Nevertheless, attempts have been made time and again by several workers to investigate and explore the use of newer materials in bad taste abatement and good taste enhancement (Table 2).


II) Granules / Powders:


Granules for reconstituting as liquids (e.g. sachets, sprinkle capsules & powders) hold a high share of pediatric and geriatric market. A large number of patents on the topic highlight the significance of the same. Thus taste masking of granules becomes an important priority in product development and varied technologies and methodologies exist for the same as illustrated below. Hayward et al.35 have reported a granular composition for taste masking comprising of drug core of a NSAID and methacrylate ester copolymers as coating agents for taste masking.  The method comprises of coating the drug cores with separate layers of aqueous dispersions of the copolymers. Granules of the invention could be used in the preparation of chewable tablets, which had good palatability and bioavailability.


Kishimoto et al.36 used mannitol and lactose in different weight ratios (1: 1.5 - 1:5) as coating materials for masking bitter taste of solid drug preparations.


Yajima et al.37 in their patent have described a composition comprising of a drug with unpleasant taste of polymer solution and D-crystals of monoglycerides.  Eudragit E (100 g) was dissolved in melted stearic acid monoglyceride (600 g) and then Erythromycin (300 g) were added to the mixture to obtain a powder, which was again mixed with sorbitol, magnesium oxide and starch to give taste masked granules of Erythromycin.


Danielson et al.38 invented a dosage form comprising granules containing the histamine receptor antagonist which are provided with taste masking coating comprising a water insoluble, water permeable methacylate ester copolymer in which the coating is applied to the granules in an amount which provides a taste masking effect for a relatively short period during which the composition is being chewed by a patient but which allows substantially immediate release of the histamine receptor antagonist after the composition has been chewed and ingested.


Kumar39 provided a means and method for manufacturing palatable drug granules using a polymer having at least one free carboxyl group and poly vinyl pyrolidone.


III) Liquids:


They present a major challenge in taste masking because the majority of pediatric preparations are syrups and suspensions although, the aforementioned methodologies have- also had been used for improving liquid taste and few patents in this area are worth mentioning.  Nakona et al.40 masked the bitter taste of vitamin B1 derivatives such as dicethimine by formulating with menthol and or polyoxyethylene, polyoxypropylene for formulating oral liquids. Osugi et al.41 in their invention subjected oral liquids containing Diclofenc and its  salts to heat treatment in the presence of glycine, glycerrhizinic acid or salt thereof to mask the bitter taste and to prevent the irritation of the throat upon oral administration.


Meyer et al.42 used prolamine , applied as single coating in weight ratio 5% to 100% relative to active substance being coated result in the production of a liquid suspension which effectively masked the taste of orally administered drugs which are extremely bitter. Prolamine coating does not restrict the immediate bioavailbility of the active substance Prolamine coating is effective in masking the taste of antibiotics, vitamins, dietary fibers, analgesic, enzymes, and hormones.


Pharmaceutical composition comprising polyhydric alcohol based carrier to mask the bitter taste of a drug were reported by Swaminathan et al.43 who prepared the liquid containing cimetidine, talin, peppermint oil and glycerol.


Morella et al.44 invented a liquid suspension of microcapsules taste masked as a function of a polymer coating and the pH of suspended medium at which pharmaceutically active ingredients remain substantially insoluble.


Yu et al.45, 46 invented a liquid composition comprising a pharmaceutically active medicament coated with a taste masking effective amount of polymer blend of dimethylaminoethyl methacrelate and neutral methacrelic acid ester and a cellulose ester in an aqueous vehicle. The liquid composition utilizes a reverse enteric coating, which is soluble in acid pH of the stomach generally about 1-4 but relatively insoluble at the non-acidic pH of the mouth. The coating provides the rapid release and absorption of the drug, which is generally desirable in case of liquid dosage forms.


Evaluation of Taste Masking Effect


Sensory analysis has been used in developed countries for years to characterize flavors, odors, and fragrances. Historically expert provided formulation scientist with subjective data on the composition of one product with another. Nowadays, sensory analysis employs objective or analytical methods and subjective or hedonic method 24 ( Table 3).


Soutakagi, et al.47 invented a multichannel taste sensor whose transducer is composed of several kinds of lipid/polymer membrane with different characteristics, which can detect taste in manner similar to human gustatory sensation. Taste information is transformed into a pattern composed of electrical signals of membrane potential of the receptor part. It was reported that suppression of bitterness of Quinine and a drug substance by sucrose could be quantified by using multi channel taste sensor. The present method can be expected to provide new automated method to measure the strength of drug substance in place of sensory evaluation.


Evaluation of the taste masking effect from coated microsphere can de done by determining the rate of release of the drug from the microspheres. Similarly for evaluating the taste masking effect by ion exchange resin, the drug release rate can serve as an index of the degree of masking achieved. Other methods include evaluation by a trained flavor profile panel and time intensity method in which a sample equivalent to a normal dose was held in mouth for 10 seconds. Bitterness level are recorded immediately and assigned values between 0-319.

Conclusion

There are number of technologies available which effectively mask the objectionable taste of drugs but require skillful application which 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.


References for Taste Masking of Pharmaceuticals


 1.   Adjei, A, Doyle R., Reiland, T., In Swarbrick, J., Boylan, J.C., Eds; Encyclopedia of Pharmaceutical Technology, Vol.6, Marcel Dekker, New York, 1992, 117.


2.    Billany, M.R.J. In; Aulton M.E., Eds; Pharmaceutics; The science of Dosage form Design, International Edition, Churchill Livingstone, New York, 1996, 263.


3.    Catania, J. S., Johnson, A. D., U. S. Patent 5633006, 1997.


4.    Nelson, S. L.,  U.S. Ptent 5766622, 1998.


5.    Eby III, Georage, A.,  U.S. Patent 5002970, 1991


6.    Pandya,H.B., Callan,T. P., U.S. Patent 5.837, 286, 1998.


7.    Corbo, M. Desai, J., Patell, M.,  U.S. Patent 6.663.893, 2003.


8.    Friend, D. R., Ng, Steve, Sarabia, R. F., Weber T. P., Geoffory,J., U.S. Patent, 6, 139.865, 2000


9.    Augello,M.,Dell, S.M.,Reier, G.E.,Stamato, H.J., DiMemmo,L. M., U.S. Patent, 6099.865,2000


10.  Cuna, M., Lorenzo, M.L., Vila-Jato, J.L., Torress D., Alonso, M.J., Drug Dev. Ind. Pharm., 1997, 23(3), 259.


11.  Kato, M., Japan Patent, 8259466, 1996.


12.  Maccari, M., Calanchi, M., In Kydonieus, A.F., Eds; Controlled Release Technologies, Methods, Theory and Applications, 1st edition, Vol. 2, CRS Press, Incl., Boca, Raton, Florida, 1980, 113.


13.  Yajima, T., Nogata, A., Damachi, M., Umeki, N., Chem. Pharm. Bull, 1996, 44(1), 187.


14.  Sugao.H., Yamazaki, S., Shizozawa, H., Yano.K., J. Pharm. Sci., 1998, 87, 96.


15.  Udea M., Nakamura, Makata, H. & Kawashima, Y., J. Microencapsulation, 1993, 10(4), 461.


16.  Yekta, Ozer & A. Atilla, Hincal, J. Microencapsulation, 1990, 7(3) 327.


17.  Cherukuri,S. R., Chau, T. K., Raman, K. P., Orama, A. M., U.S., Patent, 5004595, 1991


18.  Borodkin, S., Sundberg, D.P., J. Pharm. Sci., 1971, 60(10), 1523.


19.  Roy, G. M., Pharm. Tech., 1994, 62


20.  Manke, S.P. & Kamet, V.S., Indian J. Pharm. sci., 1991, 43, 209


21.  Gao, R., Shao, Z. J., Fan, A. C., Witchey-Kshmanan, L. C., Stewart, D. C.,  U.S. Patent, 6,514,492, 2003


22.  Motola, S., Agisim, G, R., Mogavero, A..,  U.S. Patent 5024997, 1991.


23.  Ueno, M., Japan Patent, 0411865, 1992


24.  Adjei, A, Doyle, R., Reiland, T., In; Swarbrick, J., Boylan, J.C., Eds; Encyhclopedia of Pharmaceutical Technology, Vol. 6, Marcel Dekker, New York, 1992, 130.119.


25.  Popescu, M. C., Metz, E. T.,  U.S. Patent, 5009819, 1991


26.  Fuisz, R.C., U.S. Patent, 5028632, 1991.


27.  Amita Nanda, R. Kandarapu & Garg, S., Indian J. Pharm., Sci., 2002, 64(1), 10


28.  Rosoff, M., In; Liberman, H.A., Rieger, M.M., Banker, G.S., Pharmaceutical Dosage form, Disperse System, 1st Edition, Vol.1, Marcel Dekker, New York, 1988, 259.


29.  Masahiro, Y., Gakao, M., Japan Patent, 11349492, 1999.


30.  Yoshimi, S., Kiyomi, S., Hiroshi, F., Yasuhiko, N, Chem.Pharm.Bull.,1996, 44(2), 399


31.   Namiki, T., Tokagi, N. Japan Patent, 09052850, 1997.


32.  Lulei, 4., Eraden, G., Nahed, H., Drug Dev. Ind. Pharm., 1997, 23(10), 1007


33.  Bettman, M.J., Percel, P.J., Powell, T.C., U.S. Patent 5639475.


34.  Kaneko, K., Kanada, K., Yamada, T., Miyagi, M., Saito, N., Ozeki, T. Yususa, H., Kanaya, Y., Chem. Pharm. Bull., 1997, 45(2), 1063.


35.  Hayward, M., U.S. Patent, 37277, 1998.


36.  Kishimoto, A., Okamoto, K., Japan Patent, 09143100, 1997.


37.  Yajina,T.,Ishii, K.,Itai, S., Nemoto, M., Sultake, K., Tukui, N., PCT. Inl. Appl. WO 963428,19.


38.  Danielson, D. W., Shah,S. A.,  U.S. Patent, 6, 270807.


39.  Kumar,V.,  U.S. Patent, 6, 372, 259, 2002 Liquids 40-46.


40.  Nakano, H., Hasegawa, K., Japan Patent, 11139992, 1999.


41.  Osugi, T., Japan Patent 11139970, 1999.


42.  Meyer, G., Mazer, T., U.S. Patent, 5599556, 1997.


43.  Swaminathan, K., Subramania, S., Harding, R., PCT Int. Applwo, 9733621, 1997.


44.  Morella, A., Mario, P., In Hamilton, Heinicke,G.,  U.S. Patent 6197348, 2001


45.  Yu,D.,  Roche,E.,  U.S. Patent, 6586012, 2003.


46.  Yu, D., Roche, E., U.S. Patent, 648 823, 2002.


47.  Soutakagi, K.T., Koichiwada, H.Y., Kenzo, T., J. Pharm. Sci., 1998, 87(5), 552.


{mospagebreak title=Flavoring agents for taste masking: Table 1}

Table 1: Flavoring agents for taste masking


 


 



















Basic Taste



Masking agents


Sweet


Vanilla, Bubble gum, Grapefruit


Acid


Lemon, Lime, Orange, Cherry, Grapefruit


Metallic


Grape, Marsh, Mellow, Gurana, Berries, Mints


Bitter


Liquorice, Coffee, Chocolate, Mint, Grapefruit,


Cherry, Peach, Raspberry, Orange, Lemon, Lime.

{mospagebreak title=Taste masking of tablet: Table 2}

Table 2: Taste masking of tablet


 






























Sr. No.


Materials


Method used for preparing Tablet


Ref. No.


1


Gelatin, Sugar, Citric acid, Concentrated Juice, Colorants, Flavors.


A solid preparation of Acetaminophen was prepared using gumi base


31


2


A series of Eudragit polymers with difference in the frequency of the ester substituents in the chemical structure.


Polymer coating was applied on the solid dosage form and evaluated for water permeability, pH solubility, and taste masking.


32


3


Effervescent admixture of sodium bicarbonate and citric acid encapsulated with ethyl cellulose.


Microcapsules were used in formulating taste masked effervescent chewable tablets of NSAID


33


4


Sodium alginate, calcium gluconate


A core tablet of Ampirilose was prepared which was under coated with calcium gluconate and over coated with sodium alginate which led to the formation of a gel on the surface of the tablet that exhibited good taste masking effect.


34


 

{mospagebreak title=Evaluation of Taste masking: Table3}

Table 3: Evaluation of Taste masking



































Subjective Method


Objective Methods


Preference Test


Difference Test


Paired Testing


Paired Difference Test


Triangle Testing


Triangle Difference Test

Hedonic Scale Duo trio Test
Ranking Test
Analytical Test
Flavor Profile
Time Intensity Test
Single attribute test
Dilution Profile
Statistical Test
{mospagebreak title=About the Authors}

About the Authors


Varsha B. Pokharkar1*, Sanjay J. Kshirsagar2 and Laila Fatima3


1 Professor, Pharmaceutics Department, BVDU’s Poona College Pharmacy and Research Center, Erandawane, Kothrud, Pune-411 038, Maharashtra State, India.


2 Lecturer, Pharmaceutics, STES Sinhgad Institute of Pharmaceutical Sciences, Kusgaon (BK.), Lonavala, Maharashtra, India.


3 Lecturer, Pharmaceutics, Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra State, India.


* Address for correspondence


VarshaPokharkarBig.jpg
Dr. Mrs Varsha Pokharkar


is working as a Professor of Pharmaceutics in Bharati Vidyapeeth Deemed University for the past 10 years. Presently, involved in undergraduate, post-graduate teaching and Ph.D. programmes. Current areas of interest include nanoparticulate delivery Systems for drugs , peptides and vaccines; liposomal drug delivery; polymer synthesis and preformulation studies. She has several publications in national and international journals and presentations in national and international symposia.


Contact info:


Ph. No.  +91 20 25437237, Fax No. +91 20 25439383


Email: Varshapokharkar@rediffmail.com


Sanjay_J_Kshirsagar.jpg


Sanjay J.Kshirsagar

done B.Pharm. & M.Pharm. from Pune University. Currently working as Lecturer in STES Sinhgad Institute of Pharmaceutical Sciences, Lonavala, Pune, India. He had three years of teaching experience and published articles in international journals. Current area of interest includes Nanoparticles, Novel Drug with Commercial application, Mucoadhesive film.

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