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

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Presentation on theme: "Modified release technologies Orodispersible Tablets: A Review & Opportunities September, 2011."— Presentation transcript:

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

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

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? ClinicalFormulationMarketing Pregastric delivery Faster onset Better S&E Bioequivalence Local delivery Compliance Convenience Stability Ease of use New presentation Extend exclusivity Broader application USP ODT

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 Technology Platform TechnologyCompanyExample Products LyophilisedZydis ® Catalent15 commercial products Grazax Claritin LyocCephalon7 commercial products Proxalyoc Loperamide Lyoc PharmafreezeSPI PharmaceuticalsUnknown JanssenQuicksolvRisperdal Compressed TabletsAdvaTabEurandCetirizine Lactimal Orasolve / Durasolv CIMARemeron Soltab Zomig-ZMT Niravam FazaClo Orapred FlashtabEthypharmPrevacid Solutab Ibuprofen PharmaburstSPI PharmaceuticalsNot known Sugar flossFlashdoseBiovail Molded tabletWowtabYamanouchi / Astellas Hamal D

7 ODT Technologies Loosely CompressedSpray Dried Rely on the use of: o Super-disintegrants o Effervescent agents o Highly aqueous soluble excipients o Combinations of the above Uses standard tabletting process with low compression forces Can incorporate encapsulated API for taste masking or modified release Compression forces need to be minimised to prevent damage to API coating Effervescent systems can be moisture sensitive May be friable Typically comprises: Superdisntegrants e.g. Na Glycolate Bulking agent e.g. mannitol Supporting matrix e.g. gelatin Spray drying produces porous powder

8 ODT Technologies Sugar FlossMoulded Tablets Spun fibres of sacharrides (sucrose, dextrose) or polysacharrides Floss fibres blended with API + other excipients Blend is loosely compressed Requires conditioning step at elevated temperature and humidity to convert amorphous sugar fibres to crystalline Disintegration dependant on soluble sugars and porosity Use water soluble ingredients e.g. sugars Powder blend is wetted Wetted mass moulded into tablet under loose compression Moulded mass is then dried

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 SupplierProductDose Strength NovartisVarious under Theraflu and Triaminic brands Phenylephrine HCl 2.5 to 10mg Dextromethorphan HBr 5 to 20mg Diphenhydramine HCl 12.5 to 25mg PfizerBenadrylDiphenhydramine HCl 12.5mg and 25mg PfizerSudafedPhenylephrine HCl 10mg PrestigeChlorasepticBenzocaine 3mg Menthol 2mg

11 ODTs – How do they compare?

12 Technology PlatformLyophilizedCompressed TabletSugar Floss Manufacturing requirements ProcessSpecificCommon equipmentSpecific FacilitySpecificSome dedicationSpecific Product Characteristic FDA Guidance Zydis / QuickSolve LyocAdvaTabOraSolvDuraSolvFlashDose Max Tablet weight < 500mg400mg750mg 500mg600mg Taste MaskingNot specified Flavors, sweeteners, pH adjustment, ion exchange resin Taste Masked particles (Lyopan) Flavours, sweeteners, taste masked particles Flavours, sweeteners MouthfeelNot specified SmoothVariable (some gritty)Smooth Clinical Applications Not Specified BE Buccal Oral Vaccines MR (Lyopan) BE MR BE* BE *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 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 second2 seconds3 seconds Rapid Disintegration

16 Product Embossing and packaging

17 Zydis ® Technical Review Basic Formulation Composition

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

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

20 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 Zydis Formulation & Process - Key considerations Zydis ® Formulation & Process - Key considerations

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 SEMXRD 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 8 hr Cracking noted Anneal for 30 hr < 0. 4% Cracking

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 25 o C below the Tg Use Tg to justify moisture content specification with respect to storage temperature Product X At 7.5% moisture content, Tg = 61 o C Store at 40 o C, 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 T g, glass transition temperature – Small crystal structure – Hold near T e, 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 Plasma concentration ng/ml Bioavailability - Bioequivalence

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 g Phl p5) Dosing:Zydis ® once-daily dosing, start >2 month before allergy season

44 Clinical Data 2 : 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 Grazax ® ODT Case Study: Oral Allergy Vaccine

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 2011Lyopan® Fast Dissolve Technology

47 46 Dry Seal Freeze Zydis ® Technology : Pre-mix liquid & solids Dose The Zydis ® and Lyopan ® Fast-Dissolve Technology Process Lyopan ® Technology :Dispense the aqueous mixture and API separately July 2011Lyopan® 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 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 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 47 July 2011Lyopan® Fast Dissolve Technology

49 ODTs – A Review & Opportunities Questions ?

50 discover more. CATALENT PHARMA SOLUTIONS 14 SCHOOLHOUSE ROAD SOMERSET, NJ OSDrC ® is a registered trademark of Sanwa Kagaku Kenkyusho Co., Ltd Lyopan® is a registered trademark of Pantec AG THANK YOU

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