1. Taste masking of pharmaceutical active agents Supervisor Dr.Fatemeh Ahmadi Assistant Professor of Pharmaceutics Present by Dr.Farhad Mohammadi Pharm D., Assistant of Pharmaceutics PhD Shiraz University of Medical Sciences

2. 1.Introduction 2.Methods of taste masking 3.Conclusion

3. Introduction Children and adults are subject to many of the same ailments and diseases, and by necessity, may be treated with the same drugs. Adequate testing is confounded by the requirement that the formulation of the drug meets the unique needs of children. One such need is that the medicine be palatable.

4. Introduction Flavor –The perceptions arising from the senses of taste, smell, and chemical irritation combine in the oral cavity to determine flavor

5. Introduction –These perceptions are often confused and misappropriated with odor sensations, such as bubble gum or strawberry volatile compounds (flavoring ingredients in children’s medicines in the United States)

6. Introduction Odor stimuli can reach the olfactory receptors in 2 ways: –they can enter the nostrils during inhalation (orthonasal route) –travel from the back of the oral cavity toward the roof of the nasal pharynx (retronasal route)

7. Introduction Taste –Taste is the ability to respond to dissolved molecules and ions "gatekeeper to the body” Human detects taste with taste receptor cells that are clustered in to onion ‐ shaped organs called taste buds

8. Introduction Human have around 10,000 taste buds A single taste bud contain 50 ‐ 100 taste cells These are transmembrane proteins which bind to the molecules and ions that give rise to the four primary taste sensations namely salty, sour, sweet and bitter.

9. Introduction Recently, a fifth basic taste umami has been discovered. –The umami is the taste of certain amino acids (eg., mon osodium glutamate in mushrooms,…)

10. Introduction Cells that make up the taste buds with age wear out as a result taste buds begin to disappear from roof and the sides of the mouth except taste buds that’s are located over tongue. Remaining taste buds becomes less sensitive.

11. Introduction Researches have been proved that that smoking and eating of scalding food may damage to taste buds. This lacking of taste may lead to loss of appetite and poor nutrition.

12. Introduction Major progress in taste recognition : (2 different strategies) 1.salty & sour taste ion channels serve as receptors 2.sweet, umami & bitter G-protein-coupled receptors These interactions cause electrical changes & neurotransmission signals.

13. Introduction Acids are mainly stimulated sour taste & most of organic & some inorganic compounds such as Mg & Ca produce bitter sensation

14. Introduction There are many bitter receptors because there are so many structurally different compounds that are potentially harmful »» main problem of drug formulation pharmacologic efficacy Chemical structure of a drug bitterness then it cannot be modified to increase it palatability.

15. Introduction research has focused on 3 alternatives to reducing or eliminating bitter tastes: 1.Bitter blocking (pharmacologic antagonism of bitter compound activation or transduction pathways) 2.Bitter masking (psychological interference with bitterness perception) 3.Reduction of drug solubility in saliva (a balance between reduce solubility & bioavailability must be achieved)

16. Introduction Taste masking technology includes two aspects: –Selection of suitable taste masking substance –Selection of suitable taste masking techniques The selection of appropriate technique is based on the –Type of drug –Rout of administration –Compatibility of drug with masking agent

17. Methods 1.Use of flavors & sweeteners –Flavoring agent can be nature or synthetic Natural: Peppermint, Lemon oil, Clove, Balsam & other distilled fractions concentrated extracts, alcoholic or aqueous solutions, syrups or spirit

18. Methods Synthetic: phosphorylated amino acid such as phosphotyrosine, phosphoserine, & phosphothreonine and mixtures, Aspartame & sodium saccharine Shalini Sharma, Shalila Lewis. International journal of pharmacy & pharmaceutical sciences,Vol 2, Issue 2, 2010

19. Methods Sweetening agents have been classified on the basis of taste that is masked 1.Sweet »» vanilla, grapefruit, bubble gum 2.Acid »» lemon, orange, cherry, lime 3.Metallic »» grape, gurana, mellow, berries mint 4.Bitter »» liquorice, raspberry, chocolate, coffee

20. Methods –Clove oil & calcium carbonate found to be useful for chewable or in formulation of mouth dissolving tablet –For example 1 : Ofloxacin –Aspartame Nimesulide –Camphor »Camphor significantly masked the taste of tablet with sufficient strength, friability, disintegration and dissolution 1.Vijay Sharma, Himanshu Chopra. International journal of pharmacy & pharmaceutical sciences Vol 2, Suppl 4, 2010

21. Methods 2. Coating of drug particles with inert agents –Extremely useful technique –By coordinating right type of coating material »» completely mask the taste & no adverse effect on release profile –Any nontoxic polymer that is insoluble at pH 7.4 & soluble at acidic pH, would be acceptable

22. Methods –Various inert coating agents like starch, povidone, gelatin, methylcellulose, ethyl cellulose etc. are used for coating drug particles. –One of the most efficient method is fluidized bed coating »» size of particles 50µm

23. Methods –For example 1 : Ibuprofen susp –methacrylic acid copolymer Sparfloxacin –hydroxypropyl cellulose, ethyl cellulose Diphenhydramine –hydroxypropyl methyl cellulose, Poly vinyl pyrrolidone 1.Vijay Sharma, Himanshu Chopra. International journal of pharmacy & pharmaceutical sciences Vol 2, Suppl 4, 2010

24. Methods

25. Methods 3. Taste masking by formulation of inclusion complexes –The drug molecule fits in to the cavity of complexing agent –The complexing agent decreasing oral solubility of drugs on ingestion or decreasing the amount of drug particles exposed to taste buds

26. Methods –Vander waals forces are mainly involved in inclusion complexes –β-cyclodextrin is most widely used that it is sweet, nontoxic & cyclic oligosaccharide obtained from starch – Strong bitter taste of carbepentane citrate syr was reduced to approximately 50% by preparing a 1:1 complex with cyclodextrin – Suppression of bitter taste by cyclodextrin was in increasing order of α < γ < β

27. Methods Shalini Sharma, Shalila Lewis., International journal of pharmacy & pharmaceutical sciences,Vol 2, Issue 2, 2010

28. Methods

29. Methods 4. solid dispersion system –Dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting (fusion) solvent method –This method is also called co-percipitates such as co- percipitates of sulphathiazole & povidone. –Solid dispersions using insoluble matrices or bland matrices

30. Methods –For example 1 : Rofecoxib (RXB) –Poloxamer 188 »The melting method was used to prepare solid dispersions Artemether –Mono Amino Glycyrrhyzinate Pentahydrate(GLY) »rapid disintegration of the formulated tablets in the oral cavity 1.Vijay Sharma, Himanshu Chopra,. International journal of pharmacy & pharmaceutical sciences Vol 2, Suppl 4, 2010

31. Methods 5. Microencapsulation –Means of applying relatively thin coating to small particle of solid, droplets of liquid & dispersion with various coating agents –Coating agents: gelatin, povidone, HPMC, ethyl cellulose, bees wax, carnauba wax, acrylics & shellac

32. Methods –Bitter tasting drugs can first be encapsulated to produce free flowing microcapsules which can then be compressed into tablets –Microencapsulation methods including: Air suspension Coacervation Phase sepration Spray drying Spray congealing Pan coating Solvent evaporation Multiorifice centrifugation technique …

33. Methods Shalini Sharma, Shalila Lewis., International journal of pharmacy & pharmaceutical sciences,Vol 2, Issue 2, 2010

34. Methods

35. Methods

36. Methods

37. Methods

38. Methods 6. Multiple emulsions –A novel technique for taste masking –Has been prepared by dissolving drug in the inner aqueous phase of w/o/w emulsion under conditions of good shelf stability

39. Methods –The formulation is designed to release the drug through the oil phase in the presence of gastrointestinal fluid

40. Methods 7. Using liposomes –Has been prepared by entrapping drug into liposome

41. Methods –For example incorporating into a liposomal formulation prepared with egg phosphatidyl choline masked the bitter taste of chloroquine phosphate in HEPES (hydroxyethylpiperazine ethane sulfonic acid) buffer at pH 7.2

42. Methods For example 1 : –Quinine –Propranolol lipoprotein composed of phosphatidic acid (PA) and β ‐ lactoglobulin (LG) smallest internal droplet volume (63 μl), the initial burst release was reduced significantly 1.Vijay Sharma, Himanshu Chopra,. International journal of pharmacy & pharmaceutical sciences Vol 2, Suppl 4, 2010

43. Methods 8. Prodrugs –Chemically modified inert drug precursor, which upon biotransformation liberates the pharmacologically active parent drug –For example Chloramphenicol »» palmitate ester Clindamycin »» palmitate ester Triamcinolone »» diacetate ester

44. Methods 9. Mass extrusion method (dispersion coating) –This technology involves softening the active blend using the solvent mixture of water-soluble polyethylene glycol, using methanol and expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablets –The dried cylinder can also be used to coat granules of bitter tasting drugs and thereby masking their bitter taste

45. Methods 10. Ion exchange resin –Synthetic ion exchange resin have been used for taste masking & controlled release of drug as early as 1950 –Ion exchange resins are solid, insoluble, inert & have high molecular weight so they are not absorbed by the body –consisting of a hydrocarbon network to which ionisable groups are attached and they have the ability to exchange their labile ions for ions present in the solution with which they are in contact

46. Methods –The long-term safety of ion exchange resins, even while ingesting large doses as in the use of cholestyramine is established –The adsorption of bitter drugs onto synthetic ion exchange resins to achieve taste coverage has been well done –The most frequently employed polymeric network used is a copolymer of styrene and divinylbenzene (DVB)

47. Methods Shalini Sharma, Shalila Lewis., International journal of pharmacy & pharmaceutical sciences,Vol 2, Issue 2, 2010

48. Methods The selection of ion exchange resins is governed by functional group properties swelling ratio biocompatibility & biodegradability

49. Methods Charged drugs are normally loaded on to ion exchange resins by two methods –column method –batch method

50. Methods column method –highly concentrated drug solution is passed through a column of resin particles. Since the reaction is an equilibrium phenomenon, maximum potency and efficiency is best obtained by the column method

51. Methods Batch method –In this method the drug solution is agitated with a quantity of resin particles until equilibrium is established

52. Methods

53. Methods Shalini Sharma, Shalila Lewis., International journal of pharmacy & pharmaceutical sciences,Vol 2, Issue 2, 2010

54. Methods

55. Methods –Ion exchange resins (IER) have received considerable attention from pharmaceutical scientists because of their versatile properties as drug delivery vehicles –Research over last few years has revealed that IER are equally suitable for drug delivery technologies, including controlled release, transdermal, nasal, topical, and taste masking

56. Methods 11. Granulation –Slightly bitter tasting drug –Insoluble polymers in saliva can act as binding agent –Granules less soluble in saliva –Lowers the effective surface area of bitter substance –Oral disintegrating & chewable tablets –For example: Pirenzepine & oxybutynin »» aminoalkyl methacrylate copolymer »» extrusion method

57. Methods

58. Methods 12. Miscellaneous taste masking approaches a) By effervescent agents for dosage forms that are not dissolved in water prior to administration effervescent tablets of fentanyl & prochlorperazine were developed for buccal, sublingual, and gingival absorption. The formulation contain the drug in combination with effervescent agent to promote their absorption in the oral cavity & to mask their bitter taste

59. Methods b)Rheological modification Increasing the viscosity with rheological modifier such as gums or carbohydrates can lower the diffusion of bitter substances from the saliva to the taste buds Acetaminophen suspension »» xanthan gum (0.1 ‐ 0.2%) & microcrystalline cellulose (0.6 ‐ 1%)

60. Methods c)Continuous multipurpose melt (CMT) Technology for the continuous granulation & coating of pharmacologically active substances

61. Methods Evaluation techniques –Panel testing (human subjects) –Measurement of frog taste nerve responses –Multichannel taste sensor/ magic tongue –Spectrophotometric evaluation/ D30’s value

62. Methods Panel testing (human subjects) –5 ‐ 10 human volunteers –using reference solutions –tasteless to very bitter 0-5 –the most commonly used technique

63. Methods Measurement of frog taste nerve responses –adult bull frog –glossopharyngeal nerve is then located and dissected from the surrounding –ac ‐ amplifier and an electronic integrator –The peak height of the integrated response

64. Methods Multichannel taste sensor / magic tongue –The device has a transducer which is composed of several kinds of lipid/polymer membranes –Different response electric potential pattern are obtained for substance producing different taste qualities

65. Methods Spectrophotometric Method –known quantity of the taste ‐ masked formulation is mixed with 10 ml of distilled water –test medium is then filtered through a membrane filter

66. Conclusion Zelalem Ayenew, Vibha Puri, Lokesh Kumar, Arvind K. Bansal., Recent patents on drug delivery & formulation 2009,3,26-39

67. Conclusion

68. Conclusion Some of advantages of taste masked drugs: –Improves patient compliance –Improves stability of some drugs –Improves the therapeutic efficacy & bioavailability of certain drugs – Improves the organoleptic characteristics of drugs –Improves the solubility & onset of some drugs –The methods described can be used for bench scale as well as pilot scale also

69. Conclusion An ideal taste masking process & formulation should have the following properties: 1.Involve least number of equipments & processing steps 2.Require minimum number of excipients for an optimum formulation. 3.No adverse effect on drug bioavailibility 4.Require excipients that are economical & easily available

70. Conclusion 5. Least manufacturing cost 6. Can be carried out at room temperature 7. Require excipients that have high margin of safty 8. Rapid & easy to prepare

71. Conclusion development of taste masking methodology requires great technical skill, and the need for massive experimentation

72. References 1.Roger E. Stier,. “Masking bitter taste of pharmaceutical actives”, Scientific America. 2001;284(3):34. 2.Julie A. Mennella, Gary K. Beauchamp,. “Optimizing oral medications for children ”, Clin Ther. 2008 November ; 30(11): 2120–2132 3.Vijay Sharma, Himanshu Chopra,. “Role of taste & taste masking of bitter drugs in pharmaceuticals industries an overview”, International journal of pharmacy & pharmaceutical sciences Vol 2, Suppl 4, 2010

73. References 4.Mukesh Sumar Sikandar, Rishabha Malviya, Pramod Kumar Sharma., “Taste making: an important pharmaceutical technology for the improvement of organoleptic property of pharmaceutical active agents”, European jurnal of biological sciences 3 (3): 67-71,2011 5.Mayank Jain, Amit Pareek, Girish Bagdi, Dabeer Aahmad, Ayaj Ahmd., “Taste masking methods for bitter drug- A review”, International journal of pharmacy & pharmaceutical sciences 2010 6.Shalini Sharma, Shalila Lewis., “taste masking technologies: a review”, International journal of pharmacy & pharmaceutical sciences,Vol 2, Issue 2, 2010

74. References 7.Zelalem Ayenew, Vibha Puri, Lokesh Kumar, Arvind K. Bansal., “Trends in pharmaceutical taste masking technologies: a patent review”, Recent patents on drug delivery & formulation 2009,3,26-39 8.Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: Improving the safety & efficacy of pediatric therapies. JAMA 2003;290:905–911. [PubMed: 12928467] 9.Hoppe JE. Rational prescribing of antibacterials in ambulatory children. PharmacaEcanomlcs1996;10:552–574.

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76. References 13. Bigeard L. The role of medication and sugars in pediatric dental patients. Dent Clin North Am 2000;44:443–456. [PubMed: 10925767] 14. Riera CE, Vogel H, Simon SA, Ie Coutre J. Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors. Am Physiol Regul lntegr Comp Physiol 2007;293:R626–R634. 15. Glendinning JI. Is the bitter rejection response always adaptive? Physiol Behav 1994;56:1217–1227. [PubMed: 7878094]

77. Thanks There is no deadlock for grand people because they believe they will either find a way or make a way