FDDF Masking.pdf

the UNIVERSITY of GREENWICH Fast Disintegrating Dosage Forms & Taste Masking Dr. Dennis Douroumis School of Science  Aims Novel taste masking platforms and tradition...

the UNIVERSITY of GREENWICH Fast Disintegrating Dosage Forms & Taste Masking Dr. Dennis Douroumis School of Science  Aims Novel taste masking platforms and traditional approaches Principles and Formulation of Fast Disintegrating Dosage Forms 23-Apr-17 Pharmaceutical Sciences 2  Taste Masking Traditional Technologies & Novel Platforms 23-Apr-17 Pharmaceutical Sciences 3  Taste Buds The receptors to taste in humans, called taste buds are small chemosensory receptor cells. Sensitive to sweet, salty, bitter, sour and umami (savory) tastes Information gets to the brain via three different nerves: the facial nerve (VII), the glossopharyngeal (IX) and the vagus nerve (X) 23-Apr-17 Pharmaceutical Sciences 4  Taste masking technologies Novel Platforms Physical barrier Chemical or solubility modification Solid dispersion Fluidized bed Melt coating Reducing granulation Orally solubility of drug disintegrating tablets Spray Microencapsulation congealing Chemical derivatization Chewable Melt Tablets Supercritical extrusion Fluids Complexation (cyclodextrins/resins) Precipitation Granulation- and drying spheronization Vapor deposition 23-Apr-17 Pharmaceutical Sciences 5  Fast Disintegrating Dosage Forms (FDDFs) or Orally Disintegrating Tablets (ODTs ) Nomenclature and Labeling committee at USP: “[DRUG] Orally Disintegrating Tablets is the general form of nomenclature for tablets that disintegrate rapidly or instantly in the oral cavity” Orally disintegrating tablets are characterized by: high porosity, low density and low compaction force Creation of an in-situ suspension in the oral cavity as the tablet disintegrates and is subsequently swallowed 23-Apr-17 Pharmaceutical Sciences 6  Target quality and performance attributes for ODTs 23-Apr-17 Pharmaceutical Sciences 7  FDDF Platforms Zydis Cardinal Health Orasolv Cima Labs Durasolv Wowtab Prographarm Group Flashtab Ethypharm Flashdose Fuisz Technologies Oraquick KV Pharmaceutical Easytech Antares Pharma 23-Apr-17 Pharmaceutical Sciences 8  Superdisintegrants Sodium Starch Glycolate, Sodium Carboxymethyl Starch, Croscarmellose Sodium, Soy Polysaccharides L- Hydroxypropyl cellulose Cross linked homopolymers of N-vinyl-2 pyrrolidone Mannitol grades 23-Apr-17 Pharmaceutical Sciences 9  Polyplasdone 23-Apr-17 Pharmaceutical Sciences 10  Croscarmellose 23-Apr-17 Pharmaceutical Sciences 11  Sodium starch glycolate 23-Apr-17 Pharmaceutical Sciences 12  Critical Properties Flowability 23-Apr-17 Pharmaceutical Sciences 13  Critical Properties Compressibility 23-Apr-17 Pharmaceutical Sciences 14  Critical Properties Swelling 23-Apr-17 Pharmaceutical Sciences 15  Critical Properties Gelling 23-Apr-17 Pharmaceutical Sciences 16 23-Apr-17 Pharmaceutical Sciences 17 23-Apr-17 Pharmaceutical Sciences 18  Mechanisms of Action Wicking and swelling water transport into the tablet, disruption of interparticular matrix bonds by particle expantion 23-Apr-17 Pharmaceutical Sciences 19  Mechanisms of Action Wicking and swelling water transport into the tablet, disruption of of interparticular matrix bonds by particle expantion 23-Apr-17 Pharmaceutical Sciences 20  Mechanisms of Action Repulsion Water molecules create partial positive and negative charges – breakdown of particle – particle electrostatic forces 23-Apr-17 Pharmaceutical Sciences 21  Freeze –Drying (Zydis®) Tablet is produced by lyophilising or freeze drying the drug in a matrix Dissolves on the tongue in 2 – 3 sec Microencapsulation or complexation with ion exchange resins Lightweight, fragile, and poor stability at higher temperatures/humidity Freeze – dried drug encapsulated liposomes (Scherer) 23-Apr-17 Pharmaceutical Sciences 22 23-Apr-17 Pharmaceutical Sciences 23 Effervescent systems (Orasolv®) Drug powder coating and effervescent agents 3NaHCO3(aq) + H3C6H5O7(aq) à3H2O+CO2 + 3Na3C6H5O7(aq) Additional sweeteners and flavours Disadvantage: Low mechanical strength because of the low compaction forces Durasolv®: second generation, higher compaction forces (non – direct compression fillers) Not suitable for high drug loading AstraZeneca Zomig-ZMT/ Migraine DuraSolv® Rapimelt® 23-Apr-17 Pharmaceutical Sciences 24  Flash Flow Systems (Flashdose®) Flash – Heat Process Floss-like crystalline structure, much like cotton candy Flash – Shear Process Fuisz Technologies – Biovail Corporation Nurofen® Meltlets use Flashdose technology 23-Apr-17 Pharmaceutical Sciences 25  Chewable Tablets: Medichew® Fertin Pharma Coated or uncoted gum core - resins, elastomers, emulsifiers, fillers, waxes, antioxidants and softeners encapsulation or complexation 23-Apr-17 Pharmaceutical Sciences 26  Application of Physical Barrier or Coating 23-Apr-17 Pharmaceutical Sciences 27  Coating: Conventional Process Polymeric solutions (fluidized bed) up to 40% polymer content Double layer coating - inner layer comprises water soluble polymers (HPMC) - outer layer comprises water insoluble polymers (methacrylates) 23-Apr-17 Pharmaceutical Sciences 28  Coating: Advanced Process GatteCoat ™ (Gattefossé) technology Application of molten materials Spraying a melted lipidic ester on powders or granules (10µm layer thickness) Advantages: - Solvent-free process - Drug content up to 95% - Suitable for water soluble and insoluble drugs - Moisture sensitive drugs 23-Apr-17 Pharmaceutical Sciences 29  Spray - drying Spray drying is a transformation of feed from a fluid state into a dried particulate form by spraying the feed into a hot drying medium The spray drying process comprises four major phases - atomization of the liquid stream - vaporization/drying of the liguid stream through the drying gas - Particle formation - Particle separation and collection 23-Apr-17 School of Sciences 30  Spray -drying Use of drug/polymer organic solutions 23-Apr-17 Pharmaceutical Sciences 31  Spray -drying Highly porous powders – increased dissolution rates Increased polymer amounts (effect on release profile) Residual solvents High temperatures restriction for heat sensitive active substances 23-Apr-17 Pharmaceutical Sciences 32  Pharmaceutical advantages Increasing APIs solubility and bioavailability Drug encapsulation for controlled release dosage forms and APIs taste masking Aseptic production Particle size engineering for inhalation purposes Improved compresibility of solid dosage forms 23-Apr-17 School of Sciences 33  Microencapsulation Application of coacervation/phase separation techniques Polymers with various porosity and elastic properties Blending of microcapsules and compression to produce tablets Microcaps® - Eurand Advantages Controlled polymer amounts Coat thickness Increased drug stability Wide range of particle sizes High drug loading 23-Apr-17 Pharmaceutical Sciences 34  Supercritical Fluids Drug encapsulated microparticles One step process Advantages - Control on physicochemical properties (particle size, morphology) - homogeneity - heat sensitive drugs - increase solubility/bioavailability (amorphous drugs) 23-Apr-17 Pharmaceutical Sciences 35  A SCF is defined as a substance above its critical temperature (TC) and critical pressure (PC). The critical point represents the highest temperature and pressure at which the substance can exist as a vapour and liquid in equilibrium. 23-Apr-17 Pharmaceutical Sciences 36  Supercritical Fluids Disadvantages - increased cost - limited drug/polymer solubility in CO2 - insuficient drug loading 23-Apr-17 Pharmaceutical Sciences 37  Solubility or Chemical Modification Reduction of drug solubility in the mouth reduces the drug bitterness (Sildenafil citrate – sodium carbonate) Chemical modification (derivatization) Ibuprofen converted to ibuprofen p- hydroxyphenylurea ester or aluminium salt 23-Apr-17 Pharmaceutical Sciences 38  Inclusion Complexation & Ionic Bonding Taste masking by inclusion complexation – Cyclodextrins (CDs) CDs have lipophilic inner cavities and hydrophilic outer surfaces Interact to form noncovalent inclusion complexes Captisol: polyanionic beta- cyclodextrin derivative Ion-exchange resins: high molecular weight polymers with cationic and anionic functional groups Form insoluble adsorbates or resonates Dissociation of the drug-resin complex does not occur under the salivary pH conditions. 23-Apr-17 Pharmaceutical Sciences 39  Solid Dispersions 23-Apr-17 Pharmaceutical Sciences 40  Spray Congealing & Melt Granulation Spray congealing Drug substance is allowed to melt, disperse, or dissolve in a hot melt of other additives, Sprayed into an air chamber (below the melting point of the formulation components, Provide spherical congealed pellets Melt granulation Drug is dispersed in a molten mixture containing highly water soluble sugars Heating above the eutectic temperature and then rapid cooling to form a glassy solid. Disadvantages: Less effective for heat sensitive drugs – scale up isssues 23-Apr-17 Pharmaceutical Sciences 41  Solid Dispersions HME Hot melt extrusion Drug mixing with extrudable material (e.g. Eudragit E and PVP- VA) and optionally adding a plasticizer Interactions through hydrogen bonding bridges among drug – polymer functional groups 23-Apr-17 Pharmaceutical Sciences 42  Taste Masking of APIs Using the special chemistry of EUDRAGIT® Polymers, we can achieve fine taste masked powder by using interactions between the API and EUDRAGIT 23-Apr-17 School of Sciences 43  Taste Masking of APIs 23-Apr-17 School of Sciences 44  HME 23-Apr-17 Pharmaceutical Sciences 45  HME Example 23-Apr-17 Pharmaceutical Sciences 46  HME Advantages controllable heat distribution, high mixing efficiency, cost effective continuous processing efficient scale – up 23-Apr-17 Pharmaceutical Sciences 47  References D. Douroumis, Practical Approaches of Taste Masking Technologies in Oral Solid Forms, Expert Opinion on Drug Delivery, (2007, 2011) 23-Apr-17 Pharmaceutical Sciences 48