SUSTAINED RELEASE TABLETS USING A PVA DC FORMULATION RESISTANT TO ALCOHOL INDUCED DOSE DUMPING

SUSTAINED RELEASE TABLETS USING A PVA DC FORMULATION RESISTANT TO ALCOHOL INDUCED DOSE DUMPING Dr. Dieter Lubda MilliporeSigma is a business of Merck KGaA, Darmstadt, Germany

Agenda: Sustained release tablets using a PVA DC formulation resistant to alcohol induced dose dumping Introduction Why/ what are sustained release tablets? 1 Case study (sustained release tablets) 3 2 Tablets by using PVA DC formulation Case study (alcohol induced dose dump) 5 4 6 What is dose dumping? Wrap-up and summary: Sustained release 2 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

3 INTRODUCTION WHY/ WHAT ARE SUSTAINED RELEASE TABLETS?

Daily pill burden: (Immediate vs Sustained Release) Immediate Release Sustained Release 4 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Fast-/ Sustained-Release Schematic drawing of plasma concentration-versus-time profiles following administration of different types of controlled-release dosage forms Toxic Ineffective 5 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Types of modified release dosage forms Definitions based on EMA guidelines Modified release dosage forms Release of the API(s) at a rate or place different from that of the conventional (immediate release) dosage form. Modified Release Sustained Release Sustained release (Extended release, Prolonged release dosage forms) Dosage forms showing a slower release than that of the conventional release dosage form. Delayed release dosage forms The release of the active substance is delayed for a predefined period after administration. Delayed Release Multiphasic Release Multiphasic or programmed release dosage forms e.g. pulsatile release: intended to deliver a burst of drug release at specific time intervals. 6 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Pros & Cons of Sustained Release 1 Advantages 2 Challenges Reduced dosing frequency Better patient acceptance and compliance Reduced GI side effects Reduced potential for accurate dose adjustment Need of additional patient education Stability problems Less fluctuation at plasma drug levels Well characterized and reproducible dosage form Improved efficacy/ safety ratio (total dose is low) Fate (interaction) of polymer Dose dumping Biocompatibility 7 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Drivers for Sustained Release dosage forms Therapeutic Drivers Commercial Drivers Sustained & consistent blood level within the therapeutic window Reducing side-effects Reducing dosing frequency Improving patient compliance Optimizing performance Prolonging action Minimizing variability Enhanced bioavailability Lifecycle management of patented drugs Reformulation of marketed drugs Bypassing IP hurdle 8 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Overview of common approaches to modified release formulations Modified release Delayed Sustained Multiphasic / programmed Site-specific / Targeted Triggered Enteric coating Matrix systems Reservoir systems Osmotic systems Osmotic Ion systems exchange mechanisms Ion exchange other mechanisms other Combination of immediate + extended or delayed + extended components Prodrugs / Conjugates Biodegradable carrier / coating ph sensitive coating / matrix Eroding coating Swelling / osmotically controlled systems Bioadhesive systems ph Temperature Electrostimulation Magnetism 9 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Approaches to modified release formulations Matrix systems Swelling and Diffusion Diffusion and Dissolution / Erosion Benefits Cost-effective and easy to scale up Performance adjustable (polymer type, grades thereof, quantity) Generally lower risk of dose dumping Dosage forms divisible (dose adjustment) Drawbacks Typically a first-order release profile Due to changing surface area and diffusion layer One single polymer does not suit all drugs 10 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Matrix systems: Sustained release formulations Hydrophilic matrices Non-ionic cellulose ethers (e.g. HPMC, HPC, HEC) Nonionic homopolymers of ethylene oxide (e.g. PEO) Water-soluble natural gums of polysaccharides (e.g. xanthan gum, alginate) Water swellable, insoluble homo- and copolymers of acrylic acid Hydrophobic matrices Fatty acids and derivatives Fatty alcohols Waxes of natural and synthetic origin (e.g. polyethylene) Hydrophobic polymers (e.g. ammoniomethacrylate copolymers) Polyvinyl acetate and povidone mixtures 11 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

12 TABLETS BY USING PVA DC FORMULATION

What excipient did we use for the study? Functional excipient for sustained release oral solid dose formulations 100 % Poly(vinyl alcohol), fully synthetic, milled, with specified medium particle size n OH SEM 10,000x Parteck S R P 80 Particle technology particle engineered product range Sustained Release Polyvinyl alcohol (PVA) Medium particle size in µm 13 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Material characteristics Material Bulk density Tapped density Poly-vinylalcohol pharma grade 0.51-0.58 g/ml 0.70-0.77 g/ml Angle of repose 32-37 Mean particle size 60 100 µm (laser diffraction Dv 50 ) (target ~ 80 µm) Surface (N 2 -adsorption S BET ) Pore volume (N 2 -adsorption S BET ) 0.3-0.5 m²/g not detectable Loss on drying (3h, 105 C) 5.0% Optimized particle size regarding compressibility Optimized particle size regarding drug dissolution Compliant with Ph. Eur., USP, JPE monographs Emprove Low content of croton aldehyde specified 14 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Main benefit 1: Synthetic product 1 Excipient used for the study 2 Poly-vinylalcohol with optimized mean particle size Fully synthetic and chemically defined product Established solutions to-date Very often cellulose based polymers Thus naturally derived products Batch to batch consistency Consistent quality of the excipient supports estabisment of Quality by Design (QbD) QbD helps to minimize risks in development and manufacture Batch to batch variability Challenges in formulation and production processes May affect release performance of final product Inconsistent excipient quality poses a challenge to QbD implementation Excipient supports a consistent final product quality and Quality by Design. 15 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Main benefit 2: Cost-savings by direct compression 1 PVA based excipient 2 Other processes used Suitable for direct compression (shown in combination with MCC) Typically complex, multiple-step processes DC = Direct compression Tablet Mixing Compression Wet granulation Mixing Wetting Granulation Drying Coating Wet granulation or direct compression Tablet Multiparticulates Mixing Wetting Extrusion Spheronization Drying Sieving Mixing Coating Coated tablet Filling into capsule or tabletting process Tablet Compression Tablet / Capsule Substantial process cost savings through simple and economic process 16 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Process costs: Wet granulation vs. direct compression Wet granulation Process cost ( /kg)* Process cost ( /kg)* Direct compression 1. Weighing of ingredients 2. Blending of ingredients 3. Prep. granulation fluid 4. Granulation 5. Wet sieving 6. Drying process 7. Dry sieving process 8. Add. of external phase 0.40 1.00 /kg 0.20 1.50 /kg 0.50 0.75 /kg 1.00 2.00 /kg 0.30 0.70 /kg 1.50 3.00 /kg 0.30 0.70 /kg 0.30 0.70 /kg 0.40 1.00 /kg 0.20 1.50 /kg 1. Weighing of ingredients 2. Blending of ingredients TOTAL 4.70 10.35 /kg 0.60 2.50 /kg TOTAL Compression to tablets Potential reduction of 6 additional steps Total cost reduction up to 75%** * process cost was estimated based on available production data and own experience ** depending on the formulation/process 17 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

18 CASE STUDY WITH SUSTAINED RELEASE TABLETS

General formulation with PVA based excipient Amount in % (w/w) Active ingredient 5 50 PVA Excipient (Parteck SRP 80) 20-60 Microcrystalline cellulose 20-60 Silicon dioxide, highly dispersed 0.25 1.50 Parteck LUB MST 0.25 0.75 TOTAL 100 The PVA excipient content of the formulation should not be less than 20 % (w/w), otherwise gel forming will be inhomogeneous. The choice of the microcrystalline cellulose may have an effect on the galenical properties of the resulting tablets. The PVA excipient is designed for the formulation of sustained release oral dosage forms, and is well suitable for direct compression processes. 19 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Mode of SR action Matrix tablet before wetting Matrix tablet after wetting: swelling and surface erosion visible 20 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Release [%] Mode of SR action 12 End = Tablet is mainly dispersed Visual Tracking 9 Dissolution Time 12 Hours 6 3 Dissolution Measurement 100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 time [h] N = 3 ± sd Detection: UV 244nm 21 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Case study 1 API = Propranolol HCl Pharmaceutical use Hypertension Heart rhythm disturbances Coronary heart disease Prevention of repeated myocardial infarction Physico-chemical & physiological properties Well soluble and permeable (BCS I) Therapeutic window has to be ensured, otherwise inadequate efficacy or dangerous toxic effects For consistent effective treatment within therapeutic window, a sustained drug release over longer time periods is crucial 22 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Case study 1 Formulation details Propranolol HCl Components Amount [mg] Amount [%] Propranolol HCl 160.00 32.0 PVA Excipient 167.50 33.50 MCC 167.50 33.50 SiO 2, highly dispersed 2.50 0.50 Function Model API Hydrophilic matrix polymer Binder/ Diluent Flow Regulator Parteck LUB MST 2.50 0.50 Lubricant Total 500.00 100 Manufacturing process PVA Excipient and MCC are pre-mixed for 10 minutes in a tumbling mixer. API and silicon dioxide are added, mixed again for 10 minutes and sieved over 800 µm sieve to destroy agglomerates. Parteck LUB MST is sieved through a 250 µm sieve onto the mixture. All components are blended again for 5 minutes. Direct compression at 5, 10, 20 & 30 kn (500 mg tablets, Ø 11 mm, flat, facetted) 23 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Tablet hardness [N] Ejection force [N] Case study 1 Compressibility and Ejection force Diagram: Compressibility and ejection force Legend 300 318 600 PVA Excipient example formulation tablet hardness [N] 278 PVA Excipient example formulation ejection force [N] 200 400 100 150 200 63 0 5 10 20 30 Compression force [kn] 0 Tablet hardness was measured with n = 20 The example formulation with PVA excipient shows high compressibility and low ejection forces over a vast range of compression forces. 24 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

% of propranolol HCl dissolved Case study 1 Release profile Broad range of compression forces Release profiles different compression forces Legend 100 90 80 70 60 50 40 30 20 Compression forces 10kN / 20kN / 30kN Example formulation compression force 10 kn tablet hardness 150 N Example formulation compression force 20 kn tablet hardness 278 N Example formulation compression force 30 kn tablet hardness 318 N 10 0 0 2 4 6 8 10 12 Time [h] Dissolution procedure: USP Apparatus 2 (Paddle Apparatus), 900 ml phosphate buffer ph 6.8, 50 rpm, 37 C, detection wavelength 214 nm; n=3 PVA excipient shows a constant in-vitro release behavior over a broad range of compression forces and resulting tablet hardnesses 25 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

% of propranolol HCl dissolved Case study 1 Release profile Comparison with commercial product Diagram: Dissolution comparison with commercial product Legend 100 90 80 70 Example formulation compression force 20 kn tablet hardness 278 N Commercial product 60 50 40 30 20 10 0 0 2 4 6 8 10 12 Time [h] Dissolution procedure: USP Apparatus 2 (Paddle Apparatus), 900 ml phosphate buffer ph 6.8, 50 rpm, 37 C, detection wavelength 214 nm; n=3 The commercial product is a formulation of controlled release pellets in a hard gelatin capsule. Concentration:160 mg of API which is equivalent to the example formulation with Parteck SRP 80. The example formulation with PVA excipient shows a very similar release profile to commercial product. 26 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

% of propranolol HCl dissolved Case study 1 Stability data Stability after 12 months under different conditions 100 80 60 40 Legend t=0 25 C/60% r.h., closed, after 4 months 25 C/60% r.h., opened, after 4 months 40 C/75% r.h., closed, after 4 months 40 C/75% r.h., opened, after 4 months 25 C/60% r.h., closed, after 12 months 25 C/60% r.h., opened, after 12 months 40 C/75% r.h., closed, after 12 months 40 C/75% r.h., opened, after 12 months 20 0 0 2 4 6 8 10 12 Time [h] Tablets shows no change of in-vitro release after 12 months of storage, even under stress conditions. USP Apparatus 2 (Paddle Apparatus), 900 ml phosphate buffer ph 6.8, 50 rpm, 37 C, detection wavelength 214 nm; n=3 Samples used: tablets compressed at 20 kn 27 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Case study 2 API Diltiazem HCl Pharmaceutical use Hypertension Angina pectoris Certain types of arrhythmia Physico-chemical & physiological properties well soluble and permeable (BCS I) therapeutic window has to be ensured, otherwise inadequate efficacy or dangerous toxic effects (blood pressure/heart rate, dizziness, AV block) Diltiazem HCl To ensure an effective treatment within therapeutic window and reduce the risk of side effects, a sustained release formulation is crucial. 28 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Tablet hardness [N] Ejection force [N] Case study 2 Compressibility and Ejection force Diagram: Compressibility and ejection force Legend 300 200 211 269 600 400 Example formulation tablet hardness [N] Example formulation ejection force [N] 100 108 200 0 44 5 10 20 30 Compression force [kn] 0 Tablet hardness was measured with n = 20 The example formulation shows high compressibility and low ejection forces over a vast range of compression forces. 29 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

% of diltiazem HCl dissolved Case study 2 Release profile Comparison with commercial product Dissolution comparison with commercial product 100 90 80 70 60 50 Legend PVA Excipient example formulation compression force 20 kn tablet hardness 211 N Commercial product tablet hardness 97 N Dissolution procedure: 40 30 20 10 0 0 2 4 6 8 10 12 Time [h] Dissolution procedure: USP Apparatus 2 (Paddle Apparatus), 900 ml phosphate buffer ph 7.2, 50 rpm, 37 C, detection wavelength 237 nm; n=3 The commercial product contains 90 mg of API which is equivalent to the example formulation with Parteck SRP 80. It is a tablet formulation based on carboxymethylcellulose sodium and HPMC. The example formulation shows a similar release profile to the commercial product over a broad range of compression forces and tablet hardnesses. 30 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Benchmarking Material properties Material Bulk density [g/ml] Tapped density [g/ml] Angle of repose Loss on drying (3h, 105 C) PVA Excipient 100% PVA Excipient A Excipient B Excipient C 100% HPMC 100% HPMC 100% HPMC 0.55 0.33 0.34 0.34 0.75 0.51 0.46 0.50 34.6 (good) 42.1 (passable) 36.9 (fair) 42.2 (passable) 0.8 3.0 2.2 1.9 Optimized particle size for direct compression and dissolution properties Higher bulk and tapped density gives smaller tablets Low angle of repose supports lower tablet weight variations Lower loss on drying value for better stability The typical technical data above serve to generally characterize the excipient(s). These values are not meant as specifications and they do not have binding character. 31 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Change of mass [%] Benchmarking Hygroscopicity Diagram: Dynamic vapor sorption isotherm at 25 C 60 50 40 30 Parteck SRP 80 Excipient A Excipient B Excipient C 20 10 0 0 20 40 60 80 100 Rel. humidity [%] Parteck SRP 80 shows lower hygroscopicity in comparison to HPMC based excipients, resulting in better handling and improved stability. 32 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

Tablet hardness [N] Benchmarking Compressibility Tablet hardness vs compaction force Placebo formulation: 700 600 500 400 300 200 100 0 100 Parteck SRP 80 Excipient A Excipient B Excipient C 647 509 406 405 328 336 343 288 249 187 172 149 74 60 77 5 10 21 30 Compaction force [kn] 49.75 % PVA Excipient (Parteck SRP 80) or HPMC 49.75 % MCC 0.25 % Silicon dioxide, highly dispersed 0.25 % Parteck LUB MST Direct compression using different compaction forces (500 mg tablets, Ø 11/13 mm*, flat, facetted) Tablet hardness was measured with n = 20 * Due to the low bulk density of the applied HPMC based excipients A-C, it was not possible to manufacture a tablet with a diameter of 11 mm. New developed PVA Excipient shows improved compressibility in comparison to HPMC based excipients. 33 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

34 WHAT IS DOSE DUMPING?

What is dose dumping? Sustained release dosage forms are intended to release the drug in desired concentrations for a prolonged period of time. Therefore, they have to contain larger amounts of the drug than single-dose formulations. Dose dumping is defined as: Unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form.* *definition based on EMA draft guideline EMA/CPMP/EWP/280/96 Corr1 Meyer, R. J. and A. S. Hussain (2005). Awareness Topic: Mitigating the Risks of Ethanol Induced Dose Dumping from Oral Sustained/Controlled Release Dosage Forms. Dose dumping is a critical topic for modified release formulations! 35 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

What kinds of dose dumping is possible? Inappropriate use induced dose dumping ph-induced dose dumping Alcohol-induced dose dumping tampering grinding/crushing dose division ph effect food effect dissolved in or taken with alcoholic beverages Dose dumping is a critical topic for modified release formulations! 36 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

37 CASE STUDY ALCOHOL INDUCED DOSE DUMP

Case study 1/ Topic: Test if alcohol-induced dose dumping 0% Ethanol 40% Ethanol 5% Ethanol 20% Ethanol 10% Ethanol 38 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

% of propranolol HCl dissolved Case study 1 No alcohol-induced dose dumping Diagram: Test alcohol dependent dissolution 100 90 80 70 60 50 40 Legend PVA/MCC based example formulation HCl 0.1 M PVA/MCC based example formulation HCl 0.1 M / Ethanol 95 / 5 % (v/v) PVA/MCC based example formulation HCl 0.1 M / Ethanol 80 / 20 % (v/v) PVA/MCC based example formulation HCl 0.1 M / Ethanol 60 / 40 % (v/v) 30 20 10 0 0 2 4 6 8 10 12 Time [h] USP Apparatus 2 (Paddle Apparatus), 900 ml HCl/Ethanol medium, 50 rpm, 37 C, detection wavelength 214 nm; n=3 Samples used: tablets compressed at 20 kn There is no in-vitro dose dumping effect visible over the 12-hour release time, even in a 40 % (v/v) alcohol release medium. 39 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

% of propranolol HCl dissolved Case study 1 No ph-dependent dose dumping Diagram: Test ph-dependent dissolution Legend 100 90 80 Test: - HCl 0.1M - HCl ph 1.2 - Phosphate buffer ph 6.8 PVA Example formulation HCl 0.1 M PVA Example formulation HCl buffer ph 1.2 70 60 50 40 30 20 - ph shift HCl 0.1 M to phosphate buffer ph 6.8 PVA Example formulation Phosphate buffer ph 6.8 PVA Example formulation ph shift HCl 0.1 M (2h) --> Phosphate buffer ph 6.8 10 0 0 2 4 6 8 10 12 Time [h] USP Apparatus 2 (Paddle Apparatus), 900/1000 ml medium, 50 rpm, 37 C, detection wavelength 214 nm; n=3 Samples used: tablets compressed at 20 kn Constant in-vitro release behavior is shown in different dissolution media over a broad ph range. 40 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma

41 WRAP-UP AND SUMMARY: SUSTAINED RELEASE

Case studies Summary of findings High compressibility and low ejection forces over a vast range of compression forces Constant in-vitro release behavior over a broad range of compression forces and resulting tablet hardnesses No dose dumping effect in media with different alcohol content and of different ph Lubricants have no effect on the release profile but their choice may help to improve tablet hardness. Storage stability: no change of in-vitro release after 12 months of storage Lower hygroscopicity and better suitability for direct compression in comparison to HPMC based excipients Findings were confirmed with different APIs, including propranolol HCl, diltiazem HCl, theophylline, ascorbic acid, ibuprofen (not all data shown) 42 ExcipientFest 2016 Dr. Dieter Lubda - MilliporeSigma