ORAL DISINTEGRATION / DISPERSIBLE TABLET

pharmaceutical technologists have developed a novel oral dosage form known as orally disintegrating tablets (odts) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it water. drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms ,

1. ORAL DISPERSIBLE TABLETS PRESENTED BY: SATYAM .J. SHUKLA GUIDED BY : DR. MUNIRA MOMIN 1

2. CONTENTS Introduction Market potential of ORAL DISPERSIBLE TABLETS’s Ideal properties, advantages & disadvantages Mechanisms of ODT’s Formulation of ODT’s Excipients used in ODT’s preparation Conventional techniques for preparing ODT’s Important patented technologies of ODT’s Evaluation of ODT’s Patents of ODT’s Conclusion References 2

3. INTRODUCTION United States Food and Drug Administration ( FDA) Center for Drug Evaluation and Research ( CDER) define orally disintegrating tablets in the ‘Orange Book’ as “ A solid dosage form which contain a medicinal substance or active ingredient which disintegrates rapidly within a matter of seconds when placed upon a tongue” . European Pharmacopoeia described orally disintegrating tablets as “uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed’ and as tablets which should disintegrate within 3 min”. 3

4. $ US DOLLARS TIME IN YEARS C.A.G.R 11.5% 4 Orally Disintegrating Tablet in Global market, especially in North America, China, Europe, Southeast Asia, Japan and India,

5. THE GLOBAL MARKET CATEGORY IN ODT’s OTHERS (67%) Anti-Psychotics ( 20% ) Anti-Epileptics ( 13% ) 5

6. SYNONYMS OF ODT’s 6

7. DISINTEGRATES WITHOUT WATER LEAVE NEGLIGIBLE OR NO RESIDUE IN THE MOUTH COMPATIBLE WITH EXCIPIENTS INSENSITIVE TO ENVIRONMENT CONDITIONS MOUTH FEEL SHOULD BE PLEASANT M UST H AVE S UFFICIENT S TRENGTH ORAL DISPERSIBLE TABLET IDEAL PROPERTIES OF ODTs 7 Thakur , R.R. and Kashi , M., 2011. An unlimited scope for novel formulations as orally disintegrating systems: Present and future prospects

8. ADVANTAGES OF ODT’s Enhanced oral absorption Rapid onset of action Minimized first pass effect High bioavailability Rapid disintegration Improved taste Age specific formulation (pediatric, geriatric patient) Improved patient compliance Suitable during traveling where water may not be available CLINICAL FORMULATION PATIENT RELATED 8

9. Insufficient Mechanical Strength Unpleasant Taste Or Grittiness Requires Special Packaging Hygroscopic Larger Doses Are Difficult To Formulate DISADVANTAGES OF ODT’s 9 Chotaliya , M.B. and Chakraborty , S., 2012. Overview of oral dispersible tablets. International Journal of PharmTech Research , 4 (4), pp.1712-20.

10. Fast dissolving granules MECHANISM OF ODT DISINTEGRATION Major mechanism of ODT are : DRUG Disintegrating Agent Saliva in mouth causes disintegrating agent to swell creating channels for saliva Fast dissolving granules dissolves and tablet disintegrate 10 Brahmaiah . Formulation and evaluation of orodispersable Atenolol Maleate Tablets: A Comparative Study on Natural Super disintegrents and Synthetic disintegrents .  IJoR in Ayurveda and Pharmacy ,  5 (2), pp.185-192.

11. FORMULATION OF ODT’S 11

12. TASTE DOSE STABILITY pKA UNDESIRED SHOULD NOT HAVE BITTER TASTE DOSE SHOULD BE LESS THAN 20 mg Should have good stability in water and saliva Unionised at oral cavity Short half life drugs Should able to penetrate oral mucosa Drug requiring frequent dosing CRITERIA FOR SELECTION OF DRUG 12

13. CATEGORY ACTIVE INGREDIENT Antiasthmatic Montelukast Sodium Anticoagulants Dicoumarol, Dipyridamole, Nicoumalone, Phenindione Antidiabetics Glipizide , Tolbutamide , Glibenclamide , Tolazamide , Gliclazide , Chlorpropamide . Antigout Agents Allopurinol, Probenecid , Sulphinpyrazone . Antihypertensive Amlodipine Beyslate , Carvedilol , Benidipine , Darodipine , Dilitazem , Diazoxide , Felodipine , Guanabenz Acetate, Indoramin , Isradipine , Minoxidil , Antihistamines Loratadine , Cetrizine HCl , Cinnarizine , Triprolidine , Fexofenadine. Antiepileptics Beclamide , Carbamazepine, Clonazepam, Ethotoin , Methoin , Methsuximide , Methylphenobarbitone , Phenacemide , Phenobarbitone , Phenytoin, Phensuximide , Primidone , Sulthiame , Valproic Acid. Antiarrhythmics Flecainide Acetate, Quinidine Sulphate, Amiodarone HCl , Disopyramide . Analgesics and Antiinflammatory Agents Azapropazone , Benorylate , Diflunisal , Etodolac , Fenbufen , Fenoprofen Calcim , Flurbiprofen , Ibuprofen, Indomethacin, Ketoprofen , Paracetamol . Antibacterial Agents Benethamine Penicillin, Cinoxacin , Ciprofloxacin, Clarithromycin, Clofazimine , Cloxacillin Sodium, Demeclocycline , Doxycycline, Erythromycin, Ethionamide , Imipenem , Nalidixic Acid, Nitrofurantoin , Nalidixicacid , Rifampicin, Spiramycin , Sulphabenzamide , Sulphadoxine . Antidepressants Amoxapine , Ciclazindol , Maprotiline , Mianserin , Nortriptyline , Trazodone Anticonvulsant Lamotrigine Antifungal Agents Amphotericin, Clotrimazole , Econazole Nitrate, Fluconazole, Fiucytosine , Griseofulvin , Itraconazole , Ketoconazole, Miconazole , Natamycin , Nystatin , Sulconazole Nitrate, Terbinafine , Terconazole , Tioconazole , UndecenoicAcid Antihelmintics Albendazole , Bephenium Hydroxynaphthoate , Cambendazole , Dichlorophen , Livermectin , Pyrantel Embonate , Thiabendazole 13

14. Antimalarials Amodiaquine, Chloroquine, Chlorproguanil, Halofantrine, Mefloquine, Proguanil, Pyrimethamine, Quinine Sulphate. Antimigraine Agents Dihydroergotamine Mesylate, Ergotamine Tartrate, Methysergide Maleate, Pizotifen Maleate, Sumatriptan Succinate, Rizatriptan Benzoate, Diclofenac Potassium Antineoplastic Agents And Immunosuppressants Aminoglutethimide, Amsacrine, Azathioprine, Busulphan, Chlorambucil, Cyclosporin, Dacarbazine, Estramustine, Etoposide, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitozantrone, Procarbazine, Tamoxifen Citrate, Testolactone Antiprotozoal Agents Benznidazole, Clioquinol, Decoquinate, Diiodohydroxyquinoline, Diloxanide Furoate, Dinitolmide, Furzolidone, Metronidazole, Nimorazole, Nitrofurazone, Omidazole, Tinidazole Antiparkinsonian Agents Bromocriptine Mesylate , Lysuride Maleate, Selegiline Antithyroid Agents Carbimazole , Propylthiouracil Local Anaesthetics Lidocaine Neuromuscular Agents Pyridostigmine . Cardiac Inotropic Agents Amrinone , Digitoxin , Digoxin, Enoximone , Lanatoside C, Medigoxin Corticosteroids Beclomethasone , Betamethasone, Budesonide, Cortisone Acetate, Desoxymethasone , Dexamethasone, Fludrocortisone Acetate, Flunisolide , Flucortolone , Fluticasone Propionate, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisone, Triamcinolone Nutritional Agents Betacarotene , Vitamin A, Vitamin B2 , Vitamin D, Vitamin E, Vitamin K, VitaminC Opioid Analgesics Codeine, Dextropropyoxyphene , Diamorphine , Dihydrocodeine , Meptazinol , Methadone, Morphine, Nalbuphine , Pentazocine 14

15. Oral Vaccines   Vaccines for Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, Hiv , Aids, Measles, Lyme Disease, Travellers Diarrhea , Hepatitis A, B And C, Otitis Media, Dengue Fever, Rabies, Parainfluenza , Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina Haemorrhagic Fever, Caries, Chagas Disease, Pneumoccoccal Disease, Mumps Proteins, Peptides And Recombinant Drugs Insulin, Glucagon, Somatotropin , Calcitonins , Enkephalins , Interferons Stimulants Amphetamine, Dexamphetamine, Dexfenfluramine, Fenfluramine , Mazindol , Pemoline Sex Hormones Clomiphene Citrate, Danazol , Ethinyloestradiol , Medroxyprogesterone Acetate, Mestranol , Methyltestosterone , Norethisterone , Norgestrel , Oestradiol , Conjugated Oestrogens, Progesterone, Stanozolol , Stiboestrol , Testosterone, Tibolone 15

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17. EXCIPIENTS EXAMPLES Super- disintegrants Crosscarmellose ®, Ac-Di-Sol ®, Primellose ®, Vivasol , Crosspovidone , Soya polysaccharides Binder Povidones , polyvinyl alcohols, acrylic polymers, hydroxyl propyl cellulose Saliva stimulating agent Citric acid, malic acid, tartaric acid, ascorbic acid and lactic acid Antistatic agents Sodiumlaurylsulfate , polyoxyethylene sorbitan fatty acid esters (Tweens), sorbitan fatty acid esters (Spans), polyoxyethylene stearates Flavouring agents Peppermint flavour, cooling flavor , flavor oils and flavoring aromatic oil, vanilla, citrus oils Sweetning agents Glucose, fructose, dextrose, sucrose, and Isomaltose , sucralose(600–1000), neotame (2000–8000) 17 EXCIPIENTS:-

18. 18 Lyophilization V/S Direct compression REFERENCE:- OFFICIAL SITE OF CATALENT PHARMA SOLUTION Published on Aug 17, 2015 https://www.youtube.com/watch?v=JsYGIe3Atxc

19. Freeze Drying/ Lyophilization Moulding Spray Drying Mass Extrusion Sublimation Direct compression Melt granulation Cotton candy process Phase transition process Zydis ® Technology Orasolv ® Technology Durasolv ® Technology Frosta ® Technology Wowtab ® Technology Flashtab ® Technology AdvaTab ® Technology Nanocrystal ® Technology Advantol ® 300 Industrial approaches FOR ODT’ s CONVENTIONAL PATENTED 19

20. FREEZE DRYING / LYOPHILIZATION Lyophilization means drying at low temperature under condition that involves the removal of water by sublimation . Drug in a water soluble matrix which is then freeze dried to give highly porous structure The tablets prepared by lyophilization disintegrate rapidly in less than 5 seconds due to quick penetration of saliva in pores when placed in the oral cavity. useful for heat sensitive drugs i.e. thermo-labile substances E.g-Loratidine ( claritin reditapp ) 20

21. MOLDING T ablets are prepared by using water-soluble ingredients T he powder blend is moistened with a hydro alcoholic solvent and is molded into tablets under pressure lower than that used in conventional tablet M olded tablets are very less compact than compressed tablets. these posses porous structure that increase dissolution This technique is easy way to formulate odts since limited number of processing steps Low manufacturing cost and also accommodate high dose the final weight of tablet can easily exceed that of other production method E.g-zolmitriptan ( zolmig repimelt ) Direct compression 21

22. SUBLIMATION Porosity is improved by using volatilizing agent. V olatile substances such as camphor can be used in tableting process, which get sublimated from the formed tablet in vacuum at 80°c for 30 min after preparation of tablets. P resence of a highly porous structure in the tablet M atrix is the key factor for rapid disintegration of ODTs made by sublimation Cotton candy process I t utilizes a unique spinning mechanism to produce floss-like crystalline structure, which mimics cotton candy (matrix of polysaccharides or saccharine ) This candy flossmatrix is then milled and blended with active ingredients and excipients and subsequently compressed to ODTs. 22

23. Mass Extrusion This technology involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, methanol . E xpulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments F inally cut into even segments using heated blade to form tablets . E.g - Zolmitriptan ( Zolmig ZMT) 23

24. This technique is based on a particulate support matrix, which is prepared by spray drying an aqueous composition containing support matrix and other components to form a highly porous and fine powder. This then mixed with active ingredients and compressed into tablets D isintegrated within 20 seconds E.g - Hyoscyamine sulphate ODT Spray Drying 24

25. T ablet produced by compressing the powder containing two sugar alcohols of high and low melting point and subsequently heating at temperature between their two melting points . Phase transition process ERYTHRITOL (MP: 122 °c) XYLITOL (MP: 93-95 °c) INTERPARTICULAR BONDING INCREASES 93 °C for 15 min INCREASING IN MEDIAN PORE SIZE OF THE TABLETS Helps in faster disintegration of ODT’s Increase in tablet hardness 25

26. PATENT TECHNOLOGY Lyophilizing the drug in a matrix ( gelatin ). The product is very lightweight and fragile and must be dispensed in a special blister pack. In the freeze-dried product is too low to allow for microbial growth E.g Clartin Reditab ® ( loratidine ), Feldene ( piroxicam ) Zydis ® by R. P. Scherer Corporation (Cardinal Health, Inc.) in SWEDEN F lashtab ® Technology ® by Ethypharm , Saint Cloud, France WET + DRY granulation  before compression. R elays on the use of super disintegrates E.g Nurofen ® (ibuprofen) 26

27. Durasolv ® Technology by Cima Labs Inc U.S.A Orasolv ® Technology by Cima Labs Inc U.S.A U.S.A C ima’s first orally disintegrating dosage form. D irect compression of an effervescent agent and taste masked drug. The use of effervescence causes a tablet to disintegrate rapidly in less than 1 min on contact with water or saliva E.g - orapred ® (prednisolone), flazaclo ® (clozapine) DuraSolv is Cima's second-generation fast disintegrating tablet formulation . DuraSolv has much higher mechanical strength than Orasolv due to the use of higher compaction pressures Tablets are highly durable E.g - Nulev ® ( hyoscyamine sulphate) 27

28. WOW TAB ® Technology ( Yamanouchi Pharma , Inc . Japan) Frosta ® Technology ( Akina ) PLASTIC GRANULES  compression at low pressure  produce strong tablets with high porosity. Plastic granules = POROUS AND PLASTIC material ( Maltrin QD, Mannogem ,) + PENETRATION ENHANCER (Ethanol , Decanol )+ binder  WET GRANULATION D isintegration time - 15 to 30 sec E.g - Fortecal ® ( bilastine ) API CONSTITUTE OF 50% w/w S accharides of both low and high Moldability are used API are mixed with low Moldability saccharides  granulated with high Moldability saccharides Compression E.g - Gaster -D ® (Famotidine) 28

29. AdvaTab ® ( Eurand ) Advantol ® Technology (SPI pharma ) Microencapsulation of API + gastro soluble polymer. Mask the taste with restriction of drug dissolution in mouth cavity. Disintegrate rapidly in the mouth, typically in less than 30 seconds. E.g - Advatab CETRIZINE R equires no special manufacturing equipment or tooling F ormulations utilize a standard rotary tablet press with standard tooling under normal tableting temperature and humidity conditions Reducing the production cycle time and lowering costs 29

30. Gavaskar , B., Kumar, S.V., Sharan , G., Nagaraju , M. and Rao , Y.M., 2010. Present investigations and future prospects of oral disintegrating tablets: A review. IJPSR , 1 (8), pp.45-47. OraQuick ® Technology ( KV Pharmaceutical Co., Inc.) U tilizes its own patented MicroMask ®. MicroMask ® dissolving the sugar (sucrose , mannitol , sorbitol) + protein ( albumin or gelatin ) in suitable solvent ( ethanol, isoproryl alcohol )  solution is spray dried  highly porous granules . H eat-sensitive drugs 30 Gavaskar , . Present investigations and future prospects of oral disintegrating tablets: A review. IJPSR , 1 (8), pp.45-47

31. 31 A- Clartin Reditab ® ( loratidine ), B- Alavert ® ( loratidine ) SEM pictures of horizontal cross section of oral dispersible tablets Fu, Y., Jeong , S.H. and Park, K., 2005. Fast-melting tablets based on highly plastic granules.  Journal of controlled release ,  109 (1), pp.203-210.

32. EVALUATION General Appearance Hardness / Crushing strength Weight variation Thickness Friability Disintegration Time Dissolution test Water absorption ratio Wetting time 32

33. 33 Presently, neither USP nor the European Pharmacopoeia has defined a specific disintegration test for ODTs. The results from the  USP disintegration test do not provide a strong correlation with  in vivo disintegration times in the mouth because the test uses a disintegration medium of about 900 mL of water and a vigorously oscillating apparatus, which provide conditions far than those found  in vivo  . According to a test method reported in the 12th Annual FDA Science Forum , currently there is no  USP   in vitro  method for evaluating disintegration time for ODTs, which represents  in vivo  disintegration time in the mouth. Therefore, FDA recommends using a modified form of the  USP  disintegration test   Using a disposable syringe, 1 mL of water is delivered directly onto a tablet placed on a flat surface. Completeness of disintegration of the tablet is checked by the manual palpation of the tablet at the end of 30 s, which is set by FDA as the disintegration specification for ODTs . Park, J.H., Holman, K.M., Bish , G.A., Krieger, D.G., Ramlose , D.S., Herman, C.J. and Wu, S.H., 2008. An alternative to the USP disintegration test for orally disintegrating tablets.  Pharmaceutical Technology ,  32 (8).

34. S.N0 Title Patent Number Year 1 Orally disintegrating tablet ( Ticagrelor ) significant proportion of patients with stroke have difficulty swallowing in the acute phase, and many have ongoing problems . WO2017182589 26.10.2017 2 Multilayered orally disintegrating tablets containg drug unstable to light ( Rosuvastatin ) An oral disintegrating tablet stable to light, temperature and humidity can be provided by preparing a multi-layered tablet containing rosuvastatin US20170231989 17.08.2017 3 Orally disintegrating tablet containing ( Asenapine ) treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults US20170143670 25.05.2017 RECENT PATENTS 34 http:patentscope.wipo.int/search

35. S.N0 Title Patent Number Year 4 Tofacitinib orally disintegrating tablets use in moderate-to- severe forms of rheumatoid arthritis. It helps to decrease pain, tenderness, swelling in the joints. WO2017017542 02.02.2017 5 Orally Disintegrating Tablet of ( Nabilone ) Comprising Mannitol -Based Granules Nabilone ODTs is used to treat severe nausea and vomiting caused by cancer chemotherapy US20170014340 19.01.2017 6 Orally disintegrating dosage form for administration of (AVANAFIL), and associated methods of manufacture and use AVANAFIL ODT is used to treat impotence or erectile dysfunction US20160331687 17.11.2016 RECENT PATENTS 35 http:patentscope.wipo.int/search

36. Conclusion ODT helps to overcome some of the problems that existed in conventional solid dosage form i.e. difficulty in swallowing of tablet in paediatric and geriatric patients who constitute a large proportion of world's population. ODT may lead to improve efficacy, bioavailability, rapid onset of action, better patient compliance. Oral dispersible tablet acts like solid dosage form when outside the body and solution when administered. Their characteristic advantages such as administration without water, anywhere, anytime lead to their increased patient compliance in today’s scenario of hectic life. Considering the many benefits of ODTs, a number of formulations are prepared in ODT forms, Because of increased patient demand, popularity of these dosage forms will surely expand in future. 36

37. REFERENCES : Gavaskar , B., Kumar, S.V., Sharan , G., Nagaraju , M. and Rao, Y.M., 2010. Present investigations and future prospects of oral disintegrating tablets: A review. IJPSR , 1 (8), pp.45-47 . Wagh , M.A., Kothawade , D.P., Salunkhe , K.S., Chavan , N.V. and Daga , V.R., 2010. Techniques used in orally disintegrating drug delivery system. International journal of drug delivery , 2 (2). Thakur, R.R. and Kashi , M., 2011. An unlimited scope for novel formulations as orally disintegrating systems: Present and future prospects. Chotaliya , M.B. and Chakraborty , S., 2012. Overview of oral dispersible tablets. International Journal of PharmTech Research , 4 (4), pp.1712-20 . Velmurugan , S. and Vinushitha , S., 2010. Oral disintegrating tablets: An overview. International Journal of Chemical and Pharmaceutical Sciences , 1 (2), pp.1-12. Kuno , Y., Kojima, M., Ando, S. and Nakagami , H., 2005. Evaluation of rapidly disintegrating tablets manufactured by phase transition of sugar alcohols. Journal of controlled release , 105 (1), pp.16-22 . Bandari , S., Mittapalli , R.K. and Gannu , R., 2014. Orodispersible tablets: An overview. Asian Journal of Pharmaceutics (AJP): Free full text articles from Asian J Pharm , 2 (1). Pahwa , R. and Gupta, N., 2011. Superdisintegrants in the development of orally disintegrating tablets: a review. International journal of pharmaceutical sciences and research , 2 (11), p.2767. 37

38. Gohel , M., Patel, M., Amin, A., Agrawal, R., Dave, R. and Bariya , N., 2004. Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPs PharmSciTech , 5 (3), pp.10-15 . Gupta, D.K., Bajpai , M. and Chatterjee, D.P., 2014. Fast mouth dissolving disintegrating tablet and patient counseling points for FDDTs-A Review . Fu, Y., Jeong , S.H. and Park, K., 2005. Fast-melting tablets based on highly plastic granules.  Journal of controlled release ,  109 (1), pp.203-210. Park, J.H., Holman, K.M., Bish , G.A., Krieger, D.G., Ramlose , D.S., Herman, C.J. and Wu, S.H., 2008. An alternative to the USP disintegration test for orally disintegrating tablets.  Pharmaceutical Technology ,  32 (8). 38

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