Evaluation of Immediate Release Film Coatings with Flavor Modulating Technology Richard Edsall, Bradley Brown, Larry Engel, Michael Crowley

Evaluation of Immediate Release Film Coatings with Flavor Modulating Technology Richard Edsall, Bradley Brown, Larry Engel, Michael Crowley HOME ABOUT CONNECTED UNIQUE INNOVATIVE TASTE NUTRITION SUSTAINABILITY Outline Evolution of the solid oral dose form / ODTs incorporating MUPS What is Flavor? What is Taste? What is Flavor Modulating? Improving Texture with a co processed ODT formulation Improving Taste Development of a Flavor Modulator for a bitter API Development and Sensory Evaluation of a Model ODT with MUPS 1

Orally Dispersing Tablets Advantages Reduces swallowing issues More convenient = greater patient compliance Life Cycle Management Disadvantages Disintegration limits tablet hardness Packaging more complex Many APIs are bitter Flavor is a significant factor in finished product success Orally Dispersing Tablets with MUPS Advantages Can combine different types of pellets / use different coatings Tailored release profiles combination drugs with incompatible APIs Fast dissolution of the API / high surface area Increased bioavailability / more consistent pharmacological action Disadvantages More costly and technically complex than a gastric tablet Pellets can influence consumer appeal Visual appearance we re not used to seeing spots in medicine! Pellets may create a feeling of grit in mouth 2

Formulating an ODT with MUPS Can a secondary taste system improve patient experience with a bitter API? In some examples, MUPS with a physical barrier coating may have a bad taste Bitter APIs may migrate through the physical barrier over time Patients may chew or crush the MUPS, destroying the physical barrier MUPS may linger in the mouth To create the best patient experience it may be necessary to neutralize the taste sensation of the drug This is referred to as masking, blocking, or modulating a flavor 3

Flavor modulators are commonly used in foods Reduced Calorie Beverages Improve effectiveness of high intensity sweeteners Nutritional Beverages Mask off Notes, such as proteins, vitamins and/or minerals Energy Drinks Decrease bitterness of actives including polyphenols and caffeine Alcohol Cover a burning sensation What are flavor modulators? Flavor modulators are like flavors in that they Are Natural Flavors are based on FEMA GRAS Flavor Ingredients Approximately 1,500 volatile compounds are used in the creation of flavors. Interact with taste receptors on tongue Flavor modulators differ from flavors in that they are fairly neutral in taste. Any lingering notes in a flavor modulator can be paired well with a flavor (Citrus is one example) 5

Coprocessed ODT Performs well in sensory panel Tablets were ODT without APIs examine mouthfeel and taste of ODT base formula Ingredients Coprocessed ODT Comparator 1 Comparator 2 Comparator 3 Lactose Mannitol Crospovidone dextrose Mannitol, crospovidone polyvinyl acetate mannitol crospovidone colloidal silica sorbitol HPMC MCC Crospovidone Mouthfeel No grittiness No grittiness Gritty Mild grittiness Taste (no API) Pleasant taste Chalky taste Pleasant taste Chalky taste Coprocessing ODT creates uniform spherical particles spherical shape and uniform particle size fast flow Porous particles fast disintegration 7

Coprocessing ODT improves flow and disintegration time Coprocessed ODT Physical Blend Angle of Repose 41 50 Carr s Index 18.7 25.1 Disintegration 30 sec 50 sec Tablet weight is 200 mg placebo with 0.5% mag stearate. Tablet hardness is 40 N. Disintegration performed per USP. Outline Evolution of the solid oral dose form / ODTs incorporating MUPS What is Flavor? What is Taste? What is Flavor Modulating? Improving Texture with a co processed ODT formulation Improving Taste Development of a Flavor Modulator for a bitter API Development and Sensory Evaluation of a Model ODT with MUPS 8

Development of a flavor modulator for a bitter API Model system: Sugar spheres loaded with aspirin (ASA) Method: A 20% dispersion of 80% ASA/20% HPMC E 6 in water was applied to sugar spheres with a Glatt GPC G 6 or GEA Aeromatic Fluid Bed Coater. A weight gain of 20% coating (16% ASA by weight of spheres) was applied under nominal conditions. An aesthetic cellulosic film coat containing sample modulators was applied to varying weight gains. (Film coating consisted of HPMC E 6, TEC, and modulator applied as a 10% dispersion in water in a GEA Aeromatic) to varying weight gains. Evaluation of modulators on bitter API MUPS Modulator % in Coating % WG of coating Results 9722 10% 2% Minimal effect noted (not strong enough) (sweet modulator) 9722 10% 5% Good initial coverage, but backend bitterness (sweet modulator) 7086 15% 5% Initial bitterness present, but good coverage later (bitter modulator) 9658 10% 5% Very bitter (acid modulator) 0365 10% 5% Bitter (salt modulator) 0292 10% 5% Slight bitterness remains throughout (bitter modulator) Sucralose 3% 5% Initial sweetness followed by slightly bitter Sucrose 5% 5% Minimal initial sweetness followed by bitter 9

Modulator reduces bitterness and increases sweet perception Sweetness 8.0 7.0 Soothing 6.0 5.0 4.0 3.0 2.0 Salivation Undosed Dosed 1.0 Medicinal Mouthfeel Astringency Bitterness Development of an improved modulator based on aspirin testing Notes from the more successful candidates (particularly 0292) were combined Combined modulator was concentrated, increase effectiveness at lower doses Sucralose identified as a key ingredient due to initial sweetness contribution. Ace K (Acesulfame potassium) identified as a secondary sweetener Synergistic effect with Sucralose (different receptors involved more masking potential) 10

Outline Evolution of the solid oral dose form / ODTs incorporating MUPS What is Flavor? What is Taste? What is Flavor Modulating? Improving Texture with a co processed ODT formulation Improving Taste Development of a Flavor Modulator for a bitter API Development and Sensory Evaluation of a Model ODT with MUPS Creating a model for evaluation of texture and taste in an ODT Quinine is a bitter drug that has been used as an anti malarial and for leg cramps Bitterness of antimalarial quinine gave rise to the original gin and tonic Procedure: A solution of 6.7% HPMC E 6 and 3.3% quinine was prepared in water and applied to MCC spheres (20 40 mesh / 500 700 micron) in a GEA Aeromatic fluid bed coater to yield a 3% weight gain of quinine. A coating consisting of HPMC E 6, triethyl citrate, and 20% modulator was applied to a 10% weight gain to quinine dosed pellets. Pellets were blended with co processed ODT base, magnesium stearate, and flavor as optional to yield tablets with 2 mg of quinine per tablet. Tablets were compressed with a 10 station Globe Pharma rotary tablet press with 3/8 round tooling. 11

Sensory Evaluation of Quinine ODTs Model Ingredients in ODT base Ingredients in MUPS Control none 2 mg quinine physical barrier none 2 mg quinine with HPMC overcoat Sweetener alone sucralose and AceK 2 mg quinine Modulator alone modulator alone 2 mg quinine / modulator in overcoat Final dose form modulator and sweetener Modulator, sucralose and Ace K 2mg quinine / modulator / sucralose/ AceK overcoat Physical Barrier Alone Shows Minimal Reduction in Bitterness Sweetness 7.00 6.00 5.00 Dryness 4.00 3.00 2.00 1.00 0.00 Bitterness Metallic Burning Quinine Only Mouthfeel Physical Barrier 12

Sweeteners Alone Show Minimal Bitterness Reduction Sweetness 7.00 6.00 5.00 Dryness 4.00 3.00 2.00 1.00 0.00 Bitterness Metallic Burning Quinine Only Mouthfeel Sweeteners Alone Model Drug with Modulator Alone shows Bitterness reduction Sweetness 7.00 6.00 5.00 Dryness 4.00 3.00 2.00 1.00 0.00 Bitterness Metallic Burning Quinine Control Mouthfeel Modulators Alone 13

Sweeteners and Modulators Provide Best Decrease in Bitterness Sweetness 7.00 6.00 5.00 Dryness 4.00 3.00 2.00 1.00 0.00 Bitterness Metallic Burning Mouthfeel Quinine Only Modulators and Sweeteners Modulators Alone Key Learnings From the Sensory Panels / Conclusions ODT excipients influence taste and texture in sensory panels Sweeteners alone can decrease the perception of bitterness Modulators alone performed better than sweeteners alone at decreasing bitterness Modulators also target bitter receptors, rather than overwhelming the sweet taste sensation Best overall reduction in bitterness came from use of modulator and sweetener combination in base and MUPS FMT overcoat provided additional physical barrier protection as well as modulating capability 14