Orally Disintegrating Tablet (ODT)

1. Orally Disintegrating Tablet (ODT)

2. Why ODT? • Clinical • Improved bioavailability • Enhanced oral absorption • Minimized first pass effect • Faster onset of action • Medical • Improved Compliance • No tablet or capsule to swallow or chew • Better taste, no water needed • Technical • Accurate dosing compared to liquid products • Use common process and conventional equipment • Business • Unique product differentiation • Value-added product line extension • Provide exclusive marketing • Extend patent protection

3. Why ODT is growing very fast? • Oral Fast-dissolving dosage forms are one of the fastest growing segments in the $28 billion oral drug delivery industry • The total Fast Dissolve market could reach to 1.5 Billion by 2006 • Unmet Therapeutic needs : • Fast-Acting Medications: Drugs for pain, fever, heartburn, diarrhea, migraine, anxiety, insomnia, erectile dysfunction • Compliance-Critical Medications: Drugs for Parkinson’s disease, psychosis, schizophrenia, hypertension • Pediatric Medications: Cough/cold/allergy products, analgesics, antibiotics, antipyretics • Life Cycle management: • Drugs loosing patent protection (Innovator companies) • To gain a competitive edge over traditional generics : • To create market niche products

4. List of selected ODT products marketed in the USA

5. ODT Technologies Overview

6. “Ideal” ODT – Key Product Attributes • Does not require water for oral administration yet disintegrate and dissolve in the mouth within a few seconds • Has a Pleasant taste and mouthfeel • Does not leave any residues in the mouth after rapid disintegration • Has sufficient strength to withstand the manufacturing process and postmanufacturing handling • Allows high drug loading • Is cost effective

7. ODT main product attributes • Friability • Invivo disintegration time • Mouthfeel • Taste • Dissolution

8. Invivo disintegration time • The required time for complete disintegration in the mouth using healthy volunteers. • The end point for disintegration is the time when the tablet placed on the tongue disintegrates until no lumps remain. • Volunteers must keep the tablets motionless on their tongue.

9. Invitro disintegration time • USP method is not appropriate • No correlation with invivo DT • Experimental and noncompendial techniques

10. Tablet properties • Tablet tensile strength • T = 2F/(ПDH) • F: Crushing load, the force required to break a tablet by diametric compression • D: Tablet diameter • H: Tablet thickness • Tablet Porosity • ε (%) = (1 – M/Vρ)100 • M: Tablet weight • V: Tablet volume • ρ : Powder true density (Pycnometer measurement)

11. Tablet properties

12. Tablet properties

13. Tablet Friability • Depends on the type of manufacturing technique • Conventional Friability is meaningless for Zydis technology • Friability fails for Orasolv/Durasolv! • Friability is less than 2% for directly compressible

14. Wetting time and water Absorption ratio

15. Dissolution test • Fast disintegration does not necessary cause fast dissolution • The disintegration time of ODT in the dissolution vessel is generally less than 30 seconds and therefore not an important factor in the resulting dissolution profile in terms of discrimination. • Development of dissolution method for ODT is comparable to the conventional tablets. • USP paddle apparatus is the most suitable and common choice for orally disintegrating tablets • Taste masking drives dissolution • Dissolution data on the taste-masked drug is frequently predictive of dissolution of tableted product.

16. Ideal Dissolution profile for taste masked IR product

17. Main attributes (Friability, Disintegration time, Mouthfeel)

18. Taste Masking Technology DevelopmentKey Factors • Bioequivalency (dissolution rate) • Degree of bitterness • Unit Dose • Stability • Patent Landscape • Manufacturing Cost • Process development and scale up

19. Taste Masking Approaches • Physical methods • Spray Congealing • Spray Drying • Air suspension microencapsulation • Drug/Polymer or Wax Matrix preparation by High shear granulation • Organoleptic methods • Sweetener and flavoring agent addition

20. Taste masked Acetaminophen Spray Congealing (20% drug loading)

21. Electronic Tongue Electronic tongue = Instrumental sensory technique • Used an array of 7 cross-selective sensors (potentiometric measurement) • Detect various dissolved compounds such as bitter, sour, sweet… substances • Data processing is performed by multivariate analysis • Experiment design is important to correlate the e-tongue sensor responses to sensory data (e.g. analyze active vs placebo formulations)

22. Connector Chip The liquid sensor head Sensor set Sensor scheme • Partially selective sensors : • sensitive molecules incorporated in an organic coating • Detection method : • potentiometric detection [ delta V = f ( t ) ]

23. E-Tongue taste screening • Need to compare the active formulation vs placebo formulation • The software calculate the change of sensor responses as a distance • Project the formulations on the map • The shorter distance, the better masking efficiency

24. Principle of Data treatment for Bitterness Masking Study

25. Organoleptic taste maskingCase study: Mirtazapine ODT Tablets Flavor Screening F: Containing API P: Placebo

26. Taste map (Formulation/Placebo)

27. Formulation/Placebo distance

28. Taste panel results

29. E-tongue/Taste panel correlation Formulation/Placebo distance Bitterness rank by taste panel

30. Medicated Gums Dissolution test

31. Why Medicated Chewing Gums? • As Buccal Drug Delivery • Taste masking • Fast onset of action • Local effect • Meeting patient expectations • Marketing advantages • No need for water/Swallowing

32. OVERVEW OF THE FORMULATION • THE GUM FORMULATION INVOLVES • GUM BASE • FLAVOR • INTENSE SWEETENER • BULK SWEETENER • SOFTENER • BUFFERS • ANTIOXIDANTS • COLOR

33. Baker Perkins 3 Quart R&d Sigma Blade Mixer

34. JUWEL WLS 5007K Roller

35. WLS SA7 SCORER

36. PROCESS • Mixing • Dry blend the sweetener and buffer using PK blender. • Transfer the gum mass into the oven and soften the gum mass. • Meanwhile Preheat the mixer by running the hot water through the Jacket. • Once reached to desired temperature introduce the Gum mass and other ingredients according to the procedure and start mixing. • Transfer the mixed Gum mass into the proper container. • Condition the gum mass by storing at specific temperature for specific time.

37. PROCESS (Continue) • ROLLER • Transfer the conditioned Gum mass to start rolling to specific thickness. • Scorer • Adjust the vertical and horizontal scorer space • Transfer the rolled gum mass through the scorer

38. Gum dissolution study In order to release the active substance, medicated chewing gums have to be masticated since only insignificant amount of drug substance are expected to be released by simple diffusion. • Chew out study • Requirement for human volunteers • Lack of Chew Control • Variation in the flow and composition of subjects Saliva • Invitro methods

39. Chew-out study

40. Gum Dissolution Study Figure 1 Figure 2

41. Gum Dissolution Study Nicotine Gum release of two popular brand

42. In house method • First developed by a team of Swedish scientists and published on 1999.

43. In house method

44. Gum dissolution study • Distance of the chewing surfaces (0-20 mm) • Frequency of strokes (12-120/min) • Angle of twisting movement(5-180º) • Chewing surface have a specified roughness which is obtained by a blasting procedure. • Test cell can be filled with 20-70 mL of test medium

45. Effect of rotational angle on release

46. Effect of jaws distance

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