Shashank Jain


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Fast Dissolving Tablets.

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Shashank Jain

  2. 2. Introduction <ul><li>Why oral drug delivery is preferred ? </li></ul><ul><li>So why not continue with the traditional method of oral delivery? </li></ul><ul><li>Dysphasia </li></ul><ul><li>Unpleasent taste </li></ul><ul><li>Delayed response </li></ul><ul><li>Bioavailability problems </li></ul><ul><li>What is the solution ? </li></ul><ul><li>Oral disintegrating tablets(ODT)/FDDT </li></ul>
  3. 3. Oral Disintegrating Tablets <ul><li>According to the Guidance ‘ ODTs [should] be considered oral preparations that dissolve/disintegrate rapidly in the oral cavity, with an in vitro disintegration time of approximately 30 seconds or less ...’ </li></ul>
  4. 4. Fig.1. Rapid disintegration of a lyophilize Zydis tablet in minimal volume of water
  5. 6. Desired criteria for mouth dissolving drug delivery system <ul><li>1. Not require water to swallow </li></ul><ul><li>2. Be compatible with taste masking. </li></ul><ul><li>3. Be portable without fragility concern. </li></ul><ul><li>4. Have a pleasing mouth feel. </li></ul><ul><li>5. Leave minimal or no residue in the mouth </li></ul><ul><li>6. Exhibit low sensitivity to environmental conditions as humidity and temperature. </li></ul><ul><li>7. Allows the manufacture of tablet using conventional processing and packaging equipment at low cost. </li></ul>
  6. 7. Advantages <ul><li>1. Improved compliance/added convenience </li></ul><ul><li>2. No water needed </li></ul><ul><li>3. Better taste </li></ul><ul><li>4. Improved bioavailability. </li></ul><ul><li>5. Suitable for controlled/sustained release actives </li></ul><ul><li>6. Allows high drug loading. </li></ul><ul><li>7. Adaptable and amenable to existing processing and packaging machinery </li></ul><ul><li>8. Cost- effective . </li></ul>
  7. 8. Key ingredients to use <ul><li>Should allow quick release of drug </li></ul><ul><li>Should not impart bitter taste </li></ul><ul><li>Temperature preferred for the excipients should be between 30-35 c </li></ul><ul><li>Commom excipients- </li></ul><ul><li>Binder </li></ul><ul><li>Emulsifiers </li></ul><ul><li>Diluents </li></ul><ul><li>Disintegrants </li></ul><ul><li>Flavor and taste masking agents </li></ul>
  8. 9. 1.Binders <ul><li>Binders keep the composition of these fast-melting tablets together during the compression stage. </li></ul><ul><li>They are critical for achieving the desired sensory and melting characteristics, and for the faster release of active ingredients. </li></ul><ul><li>Provide smooth texture and disintegration characteristics to the system. </li></ul><ul><li>Examples :Fats such as cocoa butter and hydrogenated vegetable oils. </li></ul>
  9. 10. 2.Emulsifying agents <ul><li>They aid in rapid disintegration and drug release. </li></ul><ul><li>Stabilize the immiscible blends and enhancing bioavailability. </li></ul><ul><li>The range of 0.05 per cent to about 15 per cent by weight of the final composition. </li></ul><ul><li>Examples : alkyl sulfates, propylene glycol esters, lecithin, sucrose. </li></ul>
  10. 11. 3.Diluents <ul><li>Sugar-based excipients are mainly used because of their high aqueous solubility and sweetness in ODT formulations </li></ul><ul><li>Improve the textural characteristics that in turn enhance the disintegration in the mouth </li></ul><ul><li>Range of 10 per cent to about 90 per cent by weight of the final composition. </li></ul><ul><li>Such as mannitol, polydextrose, lactitol and starch hydrolysate </li></ul>
  11. 12. 4.Disintegrants <ul><li>Three main type of disintegrants used- </li></ul><ul><li>Effervescent disintegrating agents </li></ul><ul><li>Non Effervescent disintegrating agents </li></ul><ul><li>Modern approach </li></ul><ul><li>-Superdisintegrants </li></ul>
  12. 13. 1.Effervescent Disintegrating Agents <ul><li>When these agents come in contact with water they absorb water and disintegrate very quickly and impart fast dissolving property to the tablets. </li></ul><ul><li>Disadvantages- </li></ul><ul><li>Excipients shows inability to prevent moisture absorption (Controlled manufacturing enviornment) </li></ul><ul><li>The cost of ODTs is higher than the cost of standard tablets made by direct compression </li></ul>
  13. 14. 2.Non Effervescent disintegrating agents <ul><li>They have their own property which makes them enable to cause disintegration of tablets. </li></ul><ul><ul><li>Directly compressible starches (such as starch 1500) </li></ul></ul><ul><ul><li>Modified starches (such as carboxy methyl starches and sodium starch glycolate) </li></ul></ul><ul><ul><li>Starch derivatives (such as amylose) </li></ul></ul>
  14. 15. 3.Modern Approach-Superdisintegants <ul><li>Superdisintegants are generally used at a low level in the solid dosage form, typically 1–10% by weight relative to the total weight of the dosage unit. </li></ul><ul><li>Examples : </li></ul><ul><li>Crospovidone A1 </li></ul><ul><li>Crospovidone A2 </li></ul><ul><li>Crospovidone B </li></ul><ul><li>Sodium starch glycolate </li></ul><ul><li>Croscarmellose sodium </li></ul>
  15. 17. Avg. particle size and flow index for industrially used superdisintegrants . Crospovidone A2 found to be best suited .
  16. 18. Taste and flavour <ul><li>Improve organoleptic characterstic. </li></ul><ul><li>They can be- </li></ul><ul><li>a) Nutritive Sweeteners- </li></ul><ul><li>sugar, dextrose ,fructose etc. </li></ul><ul><li>b) Non Nutritive Sweeteners- </li></ul><ul><li>aspartame, sugar alcohols, sucralose etc. </li></ul>
  17. 19. Various Approaches for Fast Dissolving Tablets <ul><li>Freeze –drying or lyophilization </li></ul><ul><li>Direct compression </li></ul><ul><li>Spray drying </li></ul><ul><li>Sublimation </li></ul><ul><li>Mass extrusion </li></ul>
  18. 20. 1.Freeze drying- <ul><li>What is freeze drying? </li></ul><ul><li>Advantages </li></ul><ul><li>Non Elevated temperature </li></ul><ul><li>Less shelf life stability problem </li></ul><ul><li>Enhancing dissolution profile </li></ul><ul><li>Major technologies using this phenomenon </li></ul><ul><li>1. Zydis </li></ul><ul><li>2. Lyoc </li></ul><ul><li>3. Quicksolv </li></ul>
  19. 21. 1.1 ZYDIS (R.P. Scherer, Inc.) <ul><li>The first marketed product utilizing this technology . </li></ul><ul><li>The ideal drug candidate for Zydis would be chemically stable and water insoluble, and have a small particle size. </li></ul><ul><li>the dose is usually limited to 60 mg </li></ul>FEATURES ZYDIS COMPRESSED Speed of dispersion < 3 secs >20sec Mouth Feel Smooth Gritty Dose Handling <500mg <500mg Taste Masking yes yes
  20. 22. Disadvantage- <ul><li>Relatively expensive . </li></ul><ul><li>lightweight and fragile. </li></ul><ul><li>Stability at higher temperatures and humidities. </li></ul>
  21. 23. Steps involved in zydis technology Active drug + carrier/polymer Poured in wells of blister packs Trays of blister packs passed though liq N2 freezing tunnels Aluminium foil backing is applied on blisters blisters are packed
  22. 24. Pharmacokinetc Profile Green-Zydis 10mg, Brown-Tablet 10mg, Blue- Zydis 1.25 mg.  
  23. 25. Other Technologies involving freeze drying- <ul><li>1.2 . Lyoc (Farmalyoc,France) </li></ul><ul><li>is a porous, solid galenic form obtained by lyophilization of an oil-in-water emulsion placed directly in the blister alveolus </li></ul><ul><li>1.3 . Quicksolv (Janssen Pharmaceutica, Beerse, Belgium) </li></ul><ul><li>is a porous solid form obtained by freezing an aqueous dispersion or solution of the active-containing matrix, then drying the matrix by removing the water using an excess of alcohol (solvent extraction ) </li></ul>
  24. 26. 2.The direct-compression <ul><li>Direct compression tablet's disintegration and solubilization are based on the single or combined action of disintegrants, water-soluble excipients, and effervescent agents. </li></ul><ul><li>Advantges- </li></ul><ul><li>Low manufacturing cost </li></ul><ul><li>Better understanding of process </li></ul><ul><li>High dose can be accommodated. </li></ul>
  25. 27. 2.1. FLASHTAB <ul><li>Ethypharm (Paris, France) launched Flashtab for multiparticulate actives. </li></ul><ul><li>The simultaneous presence of a disintegrant with a high swelling force, defined as “ disintegrating agent” and a substance with low swelling force (starch, cellulose), defined as “ swelling agent” </li></ul><ul><li>Disadvantages? </li></ul>
  26. 28. 2.2. DURASOLV (Cima Labs, Inc.) <ul><li>Second generation ODT. </li></ul><ul><li>High mechanical strength. </li></ul><ul><li>Cost effective </li></ul><ul><li>DuraSolv is currently available in two products: NuLev and Zomig ZMT. </li></ul>
  27. 29. 2.3. WOWTAB (Yamanouchi Pharma Technologies, Inc.) <ul><li>The WOWTAB technology utilizes sugar and sugar-like excipients. </li></ul><ul><li>Erythritol -good tolerability, sweetening and a refreshing mouth sensation </li></ul><ul><li>Advantages : </li></ul><ul><li>High dose accommodation </li></ul><ul><li>Dissolves rapidly </li></ul><ul><li>Have adequate hardness. </li></ul>
  28. 30. 3.Spray-Drying <ul><li>Highly porous and fine powders can be produced. </li></ul><ul><li>Famous work of Allen and Wang . </li></ul><ul><li>They developed formulation by using mannitol as bulking agent, hydrolyzed or non hydrolyzed gelatin as support matrix, sodium starch glycolate as disintegrant , citric acid and NaHCO3 to enhance the disintegration and dissolution. </li></ul>
  29. 31. 4.Sublimation: <ul><li>Porous tablets exhibit good mechanical strength and dissolve quickly. Inert solid ingredients (ex: urea, ammonium carbonate, camphor, naphthalene) were added to other tablet excipients and the blend was compressed into tablet. Removal of volatile material by sublimation generated a porous structure. </li></ul>
  30. 32. Process of Sublimation-
  31. 33. Effect of volatilizing agent on porosity and crushing strength Black bars- before sublimation White bars- after sublimation
  32. 34. 5.Mass Extrusion- <ul><li>Softening the active blend using solvents like methanol and expulsion of softened mass through the extruder to get a cylinder, which is then put to die system to get the tablets. </li></ul>
  33. 35. Mass extrusion instrument
  34. 36. Cont- <ul><li>Preformulation studies </li></ul><ul><li>Dissolution and disintegration studies. </li></ul><ul><li>Case study </li></ul>
  35. 37. 1. Preformulation Studies- <ul><li>These studies is important in case of direct compression method. </li></ul><ul><li>Two major concern- </li></ul><ul><li>Influence of various excipients on disintegration time. </li></ul><ul><li>Influence of compression force on friability and crushing strength. </li></ul>
  36. 38. Influence of excipient - Mannitol show good disintegration profile for an ODT
  37. 39. Influence of compaction force <ul><li>In case ODT formulation, the need to produce physically stable tablet contrast with the need to produce tablet with rapid disintegration </li></ul><ul><li>PHYSICAL STABILITY DISINTEGRATION </li></ul><ul><li>High hardness </li></ul><ul><li>Low friability </li></ul>
  38. 42. 2.Disintegration and Dissolution Studies- <ul><li>Disintegation- </li></ul><ul><li>No disintegration test mention </li></ul><ul><li>USP or EP. </li></ul><ul><li>‘ Texture Analyser’ is commonly </li></ul><ul><li>used </li></ul><ul><li>PRINCIPLE- With the help of </li></ul><ul><li>software distance-time profile </li></ul><ul><li>give the disintegration time of </li></ul><ul><li>oral disintegrating agent. </li></ul>
  39. 44. Dissolution - <ul><li>USP 2 paddle apparatus is the most suitable and common choice for orally disintegrating tablets. </li></ul><ul><li>Generally taste masking or coating agent dictaes the dissolution profile of the oral disintegrating drug. </li></ul>
  40. 45. Dissolution as a function of coating levels in zofran ODT
  41. 46. Case Study- Incorporation of “coprocessed” mannitol and microcrystalline cellulose in ODT(Glipizide) . <ul><li>Since mannitol has good aqueous solubility with negative heat of solution , it can be combined with highly compressible microcrystalline cellulose with good absorbing capacity. </li></ul><ul><li>Mannitol : MCC of 1:1.25 was found to be best suited. </li></ul><ul><li>Disintegration time was found to be 17 sec. </li></ul><ul><li>Major concern- </li></ul><ul><li>Is there any interaction between excipients </li></ul><ul><li>Dissolution profile </li></ul><ul><li>Sensory acceptability </li></ul>
  42. 47. DSC PROFILE : A= Placebo, B=Mannitol , C= Coprocessed mannitol in formulation 1, D= Coprocessed mannitol in formulaiton 2.
  43. 48. Dissolution profile of the glipizide tablet and glipizide ODT obtained from copressing of mannitol and MCC(1:1.25)
  44. 50. Major limitation- <ul><li>How to mask bitterness ? </li></ul><ul><li>- Ion exchange resins </li></ul><ul><li>-Forming microgranules </li></ul><ul><li>How to improve Bioequivalence ? </li></ul><ul><li>- Microencapsulation </li></ul>
  45. 51. How to mask bitterness ? <ul><li>1. Ion exchange resins- </li></ul><ul><li>Ion exchange resins are solid and suitably insolubilized high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium reversibly and stochiometrically. </li></ul><ul><li>Bitter cationic drugs can get adsorbed on to the weak cation exchange resins of carboxylic acid functionally to form the complex which is non bitter </li></ul><ul><li>Polystyrene matrix cation exchange resins </li></ul>
  46. 52. Ion Exchange Resin Example Strong acid cation exchange resin Amberlite IRP-69, Indion-224 Weak acid cation exchange resin Amberlite IRP-65, Indion-204, Indion-234 Strong base anion exchange resin Amberlite IRP-276 Weak base anion exchange resin Dimethyl amine resin
  47. 53. 2.Forming Microgranuales Coating with taste masking material [ethylcellulose aquaous dispersion] SEED [Fine crystalline microcellulose sphere] Layering with drug
  48. 54. a) FMCS b) layered micro granules c) Coated micro granules
  49. 55. How to improve bioequivalence ? <ul><li>Biggest challenges for an ODT that uses taste-masking polymers is achieving bioequivalence with the conventional form </li></ul><ul><li>Using a micro-encapsulation technique restricts dissolution of the API in the mouth, but allows rapid dissolution in the GI tract, thus overcoming the bio equivalence obstacle. </li></ul>
  50. 56. Microencapsulation showing restricted dissolution of API
  51. 57. Application- Proportion of fast disintegrating systems approved according to therapeutic use. Blue –japan, Red- US, Yellow- EU
  52. 58. APPLICATION DRUG PRODUCTS Antidepressant Mirtazapine (SSRI) Remeron SolTab Allergy (Asthma) Fexofenadine Allegra ODT Migraine zolmitriptan Zomig Rapimelt™ Analgesic tramadol hydrochloride ULTRAM® ODT Cancer odansetron Zofran Inflammatory disease( arthritis) prednisolone Orapred
  53. 59. Life Cycle Managament- <ul><li>The market continues to grow 20% each year, with a growing penetration of generic ODTs. </li></ul><ul><li>Both branded and generic companies are competing to get a share from more than $30 billion oral delivery system market. </li></ul><ul><li>Key – </li></ul><ul><li>Market value </li></ul><ul><li>Regulatory benefits </li></ul><ul><li>Patient value </li></ul>
  54. 60. Conclusion- <ul><li>ODT with there unique characterstics plays important role in providing patient complience, Marketing edge and regualtory benefits. </li></ul><ul><li>Although ODT target patients are generally patients with dysphagia, elderly and childrens, However with there unique characterstics (mentioned above) ODT shows potential of great future. </li></ul>
  55. 61. Thank you