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modified release technologies

modified release technologies. Orodispersible Tablets: A Review & Opportunities September, 2011. What are ODTs?. Solid dosage form. Rapid disintegration on the tongue. Oral route of administration. Fast Dissolve Dosage Form. A stable, oral dosage form

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modified release technologies

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  1. modified release technologies Orodispersible Tablets: A Review & Opportunities September, 2011

  2. What are ODTs? Solid dosage form Rapid disintegration on the tongue Oral route of administration Fast Dissolve Dosage Form A stable, oral dosage form with the dosing ease of a liquid

  3. Regulatory Definitions • US Definition • Orally Disintegrating Tablet • A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue. • Tablet weight <500mg. In-vitro USP disintegration test <30 seconds. • FDA Guidance for Industry -Orally Disintegrating Tablets (Dec 2008) • EU Definition • Orodispersible tablets • Orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed • Disintegration Test: Orodispersible tablets disintegrate within 3 mins when examined by the test for disintegration……. • European Pharmacopoeia (Ph.Eur.)

  4. Why use ODT? • Clinical ODT Formulation Marketing • New presentation • Extend exclusivity • Broader application • USP • Compliance • Convenience • Stability • Ease of use • Pregastric delivery • Faster onset • Better S&E • Bioequivalence • Local delivery

  5. ODT Technologies • Can be broadly categorised according to method of manufacture: • Lyophilised • Loosely Compressed • Other • Moulded tablets • Spray dried powders • Sugar Floss • Mass Extrusion

  6. Example ODT Technologies

  7. ODT Technologies

  8. ODT Technologies

  9. Thin Film Strips • Comprise hydrophilic polymers e.g. pullulan • Process is based on liquid casting of polymer solution to form the film • Dosage controlled by concentration of API in bulk solution and film thickness (50 to 200mm) • Once dried film is cut into single unit doses prior to packaging • During manufacture dried film must be protected from heat & humidity • Final pack must protect from moisture • Use of encapsulated API challenging due to particle size

  10. Examples, Thin Film Strips

  11. ODTs – How do they compare?

  12. ODTs – How do they compare? *CIMA / Cephalon have also developed Oravescent, on ODT designed to facilitate oral transmucosal delivery.

  13. Freeze Dried ODT - Zydis®

  14. Zydis® Product Characteristics • Disintegrates in less than 10s, typically less than 5s • Robust, can withstand transport & handling • Typical shelf-life of up to 2 - 3 years (physical & chemical) • Improved stability for some compounds due to freeze drying • Packaging integral part of product design, robustness, stability & child resistance • Applications: • Bioequivalence to conventional tablet • Pre-gastric absorption • Improved onset of action • Topical oral delivery

  15. 1 second 2 seconds 3 seconds Rapid Disintegration

  16. Product Embossing and packaging

  17. Zydis® Technical Review • Basic Formulation Composition

  18. Solution or Suspension matrix filling nozzle freeze freeze dry pores blister rapid water permeation and dispersion drug in minimum volume of liquid The Zydis® Process - Schematic

  19. Zydis® Manufacturing process Mix Form Blister Dose Freeze at low temperature Freeze Dry Seal Pack

  20. Zydis® Formulation & Process - Key considerations Dose and Solubility • Insoluble API ~ 400mg • Soluble API ~ 60mg • Lyopan will increase dose capability Drug particle size • Zydis d90 ~ 30um • Lyopan no limits Stability / Compatibility • Physical & chemical stability considerations Taste Masking Strategies

  21. Formulation - Taste Masking • Flavors • Appropriate selection to mask bitterness and match marketing requirements • Sweeteners • High intensity sweeteners routinely used • Aspartame • Acesulfame K • Sucralose • Ion Exchange Resins • Coated APIs - Lyopan

  22. Zydis® – Taste Masking Example of Ion-Exchange Taste Masking % Drug in Solution vs pH for Cationic Drug : IRP64 Complex (1:3)

  23. Zydis® – Taste Masking Example of Drug Encapsulation for Taste Masking Integrity of Reverse Enteric Coating at pH 8 over 48 hours Aqueous Processing

  24. Zydis® Stability Considerations • Zydis Stability • Must be chemically stable for up to 48 hours in aqueous matrix • Potential for hydrate / polymorphic transitions • Employ pH optimisation to stabilise • Employ low temperature processing conditions ~ 10˚C • Matrix has stabilising affect • Matrix can be optimised to minimize crystal changes

  25. Zydis® Evaluation SEM XRD DSC DVS

  26. Scanning Electron Microscopy

  27. Zydis® Process -Technical Considerations • Frozen hold (Mannitol Crystallisation) on Cracking Anneal for 0.25hr Cracking noted Anneal for 30 hr < 0. 4% Cracking Anneal for 8 hr Cracking noted

  28. Zydis® Process -Technical Considerations • Moisture, Tg and Storage Conditions • Product stored at or close to the Tg, matrix loses its strength and product will shrink • Recommend to stored at least 25oC below the Tg • Use Tg to justify moisture content specification with respect to storage temperature • Product X • At 7.5% moisture content, Tg = 61oC • Store at 40oC, propensity for shrinkage • Store at ambient,product physically stable

  29. Zydis® Process –Freeze Drying

  30. Zydis® Process –Eutectic Freezing Curve • 5% Mannitol -3.2°C • 5% Potassium chloride -11.0°C • 5% Sodium chloride -21.1°C • 1% Trehalose -28.4°C • 1% Glucose -41.4°C • 1% Fructose -48°C

  31. Zydis® Process –Sublimation • Water: triple point 0.04°C, 6.11 mbar • Menthol: melting point 42-44°C, vapor pressure 1.1 mbar • Ammonium bicarbonate: triple point ~50-60°C, ~500 mbar

  32. Zydis® Process –Freezing Rate • Develop freezing process to optimize crystal structure • Large crystal  rapid disintegration, short freeze-drying cycle • Small crystals  product strength and robustness • Annealing of crystal structure after freezing • Amorphous structure (soluble actives)  crystalline structure • Hold above Tg, glass transition temperature • Small crystal structure • Hold near Te, eutectic melting point

  33. Examples of Technical Opportunities

  34. Clinical Considerations • Bio equivalence • Pregastric Delivery • Faster Onset • Better S & E • Nano particle delivery system • Proteins / Peptides / Vaccines

  35. Bioavailability - Bioequivalence Plasma concentration ng/ml

  36. Disintegration vs Water Volume

  37. Zydis® Pre-Gastric Absorption • Pre-Gastric Absorption - Efficacy & Safety of Selegiline

  38. Metabolites of Selegiline Mean AUC (Nm.h) Zydis Selegiline (1.25mg) Selegiline Tablets (10mg)

  39. Nanoparticle Formulation using Zydis® Goals: 1. Nanoparticle stabilization during wet milling AND freeze drying 2. Use low conc. of stabilizers that do not have adverse taste 3. Rapid dispersion of nanoparticle solid dosage form

  40. Nanoparticle Stability in Zydis®

  41. In vitro dissolution of nanoparticulate Zydis®

  42. Zydis® for Peptides & Proteins • Solid, unit doses presented in protective pack • Freeze drying – proven technology for stable protein formulations • Low temperature processing minimises potential for manufacturing losses • Solution / suspension dosing achieves good content uniformity • Solid dosage form aids long term stability • Liquid processing facilitates containment of potent drugs in production

  43. Grazax® ODT Case Study: Oral Allergy Vaccine • Product: Oral vaccine alternative to injection • Active: Grass Pollen Extract from Phleum pratense (timothy grass) • Dose: 75,000 SQ-T (Equiv. ~15 mg Phl p5) • Dosing: Zydis® once-daily dosing, start >2 month before allergy season

  44. Grazax® ODT Case Study: Oral Allergy Vaccine • Clinical Data2: • 30% reduction in rhinoconjunctivitis symptoms score & • 38% reduction in medication score compared with placebo. (P<0.0001). 2 Dahl et al J Allergy Clin. Immunol. 2006, 1118, p434

  45. Activity Retained in Zydis® for 36 Months Allergen Activity (Phl p5) in Zydis® vs. Time

  46. What is Lyopan® Fast - Dissolve Technology? • Patented technology covering the manufacture of fast dissolve lyophilized dosage forms • Designed by University Basel and Pantec, a Swiss company linked to Rohrer, the equipment supplier in 2008 • The process involves dosing powder into blisters and then adding a small amount of water, prior to freezing to bind the unit together • It is then frozen and dried like Zydis® Fast Dissolve Tablets 44 July 2011 Lyopan® Fast Dissolve Technology

  47. The Zydis® and Lyopan® Fast-Dissolve Technology Process Zydis ® Technology : Pre-mix liquid & solids Dose Freeze Lyopan ® Technology :Dispense the aqueous mixture and API separately Seal Dry July 2011 Lyopan® Fast Dissolve Technology

  48. Better Treatments with the combined Lyopan® and Zydis® Fast-Dissolve Technologies • Catalent has exclusive rights to Lyopan technology • Patent protected technology • Catalent will be both a development and manufacturing partner • Partnership complements the current Zydis technology • A wider group of molecules can now be formulated as a fast-dissolve lyophilized ODT more molecules • Lyopan adds innovation to proven fast dissolve technology • Both processes produce a fast dissolve which disperses in as little as 10 seconds • Increased options for taste masking • Options for enteric coating or controlled release • Enables formulation of molecules at a higher dose ( >200 mg ) • Potential to improve manufacturing efficiency by reducing cycle times better treatments • Catalent will introduce Lyopan technology in the upcoming months • Pantec will continue to collaborate with Catalent • Non-GMP POC will be available • First GMP line anticipated to be established at the Zydis Swindon UK manufacturing site over next year • reliably supplied 47 July 2011 Lyopan® Fast Dissolve Technology

  49. ODTs – A Review & Opportunities Questions ?

  50. THANK YOU discover more. CATALENT PHARMA SOLUTIONS14 SCHOOLHOUSE ROADSOMERSET, NJ 08873 + 1 866 720 3148 www.catalent.com OSDrC® is a registered trademark of Sanwa Kagaku Kenkyusho Co., Ltd Lyopan® is a registered trademark of Pantec AG

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