New and Emerging Uses of Polymeric Excipients to Overcome Drug Delivery Challenges

Transcription

1 New and Emerging Uses of Polymeric Excipients to Overcome Drug Delivery Challenges Thomas Dürig 1

2 Critical Importance of Excipients Biopharmaceutical factors modulated by excipients Dissolution API solid state Luminal reactions Stability of the API API surface area ph API particle size API solubility Enzymatic reactions Bile salts Product disintegration Fraction of dose absorbed Transit times Intrinsic permeability Absorption 2 Adapted from Kubbinga et al Eur J Pharm Sci 61 (2014) 27-31

3 2 Challenges in Drug Delivery and Dosage Form Development Low Biovailability/ Solubility 70% of oral drug pipeline solubility challenged Fewer compounds progressing through early stage development Growth in solid dispersions and alternate technologies Importance of Patient Compliance CR for reduced dosing & side effects Pediatric and geriatric friendly (taste) ease of us Rise of abuse resistant dosage forms Improved patient monitoring - Ingestible microchips Efficient Manufacturing processes Continuous processing Rise of twin screw hot melt extrusion Other Twin screw extrusion Re-evaluation of direct compression processes Parenteral drug delivery Rise in biopharmaceutical Need to stabilize proteins and peptides Aggregation inhibitors Also stabilizing and solubilizing small molecules oral bioavailability enhancers for peptides and proteins Innovation in Excipients : bioavailability, ease of administration, reduced dosing, stability 3

4 Selected Areas of Focus in Polymeric Excipient Research New and emerging uses in hot melt extrusion processing Solubilization-solid dispersions Taste masking Controlled release New and emerging uses in continuous manufacturing and direct compression New and emerging uses in injectable and liquid systems Stabilizing API s Solubilizing API s Protein excipient interactions 4

5 Hot melt extrusion for solubilization / solid dispersions Individual drug molecules dispersed in solid polymer phase Supersaturated concentration Intrinsic drug solubility HPMCAS, HPMC & Copovidone are leading solid dispersion polymers but. 5

6 New HPMC AS Analogs: Improved Thermal Processing for Hot Melt Extrusion A A C A A C Solid Dispersion of Drug in the polymer B B D D HPMC AS New Analog Crystalline Drug 6

7 Improved melt rheology of new HPMCAS analogs Lower viscosity of AquaSolve HPMCAS samples as temperature increases New grades melt extrudable at lower temperatures than commercial grade 7

8 New HPMC AS Analogs: Improved Solubilization A H S M M H A A S M Drug molecule Original HPMC AS New synthesis method A H H A S M S M A S Better interaction and solubilization New HPMC AS with more selective and better drug interaction ability 8

9 Ezetimibe Concentration (µg/ml) Improved Solubilization and Sustainment Rapid Crystallizer Ezetimibe AquaSolve HPMCAS new grade AquaSolve HPMCAS new grade AquaSolve HPMCAS HG Ezetimibe Time (minutes) Ezetimibe has a high recrystallization potential giving lower overall solubility (8.5 µg/ml) Solid Dispersions were prepared as 60% ezetimibe load New HPMCAS grade samples show >7X solubilization enhancement of ezetimibe compared to drug alone 9

10 New HPMC Analogs: Improved Thermal Processing for Hot Melt Extrusion Affinisol HPMC* altered synthesis method results in enhanced thermoplasticity and greater hydrophobicity. T g C vs 180 C. Extrudable at 150 C. More organosoluble Low and high molecular viscosity types for solubilization and controlled release 10 *Third party trade name

11 Pressurized CO 2 -Reversible polymer plasticizer and foaming aid in HME for improved solubility Inexpensive, non toxic, non flammable high purity solvent Good solvent for most small non-polar molecules P-Co 2 acts as a plasticizer by reducing T g for most polymers Secondary foaming effects can be achieved resulting in highly porous structures with desirable mechanical and dissolution properties. 11 (courtesy M. Repka, Univ of Missipppi)

12 Case Study- Ketoprofen and HPC API Polymer Extrusion process Zone / Temp. ( o C) Screw speed (rpm) Torque (Nm) Ketoprofen 15% w/w Klucel HPC ELF without CO 2 All Zones 140 with CO 2 Zone 2-5 (140 ) & rest * Processing Temperature for extrusion with P-CO 2 was lower by 20 o C for all zone except Zone 2-5 A B Polarized Light Microscopy Images (3X Magnification) of Klucel ELF HPC (A) Without CO 2 (B) With CO 2 Klucel ELF HPC Without CO 2 injection With CO 2 injection Surface area (m 2 /Kg) Pore volume cm 3 STP

13 Drug Release Studies Ketoprofen/ELF : with CO 2 : without CO 2 : physical mixture P-CO 2 assisted HME demonstrated significant enhancement in the drug release rate 13

14 Use of Polymers in Taste Masking via HME Physical Blend HME Milling ODT Tablet Drug embedded in EC via HME Caffeine citrate and sildenafil citrate Ethylcellulose (Aqualon EC N7 ) chosen as barrier due to low mp Maintain the Crystallinity via Modified screw design Taste masked with preferable release Desirable release in Gastric via Pore forming agent Poreformers, calcium phosphate and mannitol to promote gastric release J. Pharm Sci Manuscript, in press, Morrot et al (Repka group and ASI) 14

15 Modified screw design to maintain crystallinity Temperature: C Standard Design Screw Speed: 50 rpm Torque: % Modified Screw design: Modified Design --Will help to maintain the API Mixing Zone in a crystalline form & reduce the torque 15

16 Sildenafil release from ODT tablets Oral Release (Artificial Saliva ) Both in Vitro dissolutions indicated that the optimized extruded formulation was sufficiently taste masked as well as attained desired drug release profiles. 16

17 Human Taste Panel Evaluation 0 : no taste, 1 : threshold, 2 : slightly unpleasant/bitter, 3 : bitter, 4 : moderately bitter, 5 : extremely bitter F1: 20% API + 60% EC-N7 + 5% TEC + 3% Mannitol F2: 20% API + 60% EC-N7 + 5% TEC + 15% Calcium Phosphate Note: Two HME ODT Tablets were significantly better than PM. 10 Healthy human volunteers (ages 18-42yrs) (Protocol number VIPS/2013/12). 17 (API: Caffeine citrate)

18 Extruded Solid Dispersions for Simultaneous Solubilization and Controlled Release Case study: Develop amorphous solid dispersion in pellet form to achieve 8h t 80% release for low soluble drug (Nifedipine (BCS class II) as the model drug) T m (ºC) T g (ºC) MW (g/mol) Solubility (mg /ml) ph 6.8 Buffer DI Water ph % SLS FaSSIF ph Approach: Extrusion using typical controlled release grades of HPMC (Benecel TM K type) and copovidone (Plasdone TM S-630) polymers Formulation Design Factors Drug loading level Ratio of hypromellose to copovidone Hypromellose molecular weight Pellet size Plasticizer 18

19 Hang - Glider Effect New drug delivery platform with programmable drug release while simultaneously solubilizing and preventing drug crystallization 19

20 Effect of HPMC Grade 20% drug loading 40% HPMC, 40% CoPVP K4M, K15M, K100M and K200M Molecular Weight (Dalton) for Benecel TM K4M Mw: 400,000 K15M Mw: 575,000 K100M Mw: 1,000,000 K200M Mw: 1,200,000 Higher MW of HPMC will help sustain degree of supersaturation and delay the drug release 20

21 Dissolution Stability, 40ºC/75%RH Product stable throughout 6 month accelerated stability F5: 20%API, 40%HPMC, 40% Copovidone Container closure system evaluated: 60cc HDPE bottle, 0.04 inch wall thickness F2 values > 50 throughout 6M 21

22 Use of Excipients in Continuous Processing DISPENSING DRY MIXING WET GRANULATION DIRECT COMPRESSION FLUID BED DRYER DRY GRANULATION DRY MILL MIXING (LUBRICANT) TABLET PRESS TABLET COATER 22

23 Continuous Granulation of Acetaminophen Leistritz ZSE 18HP Extruder GEA/Niro ConsiGma T* -1 Glatt 5L High-shear Granulator2 Feed Rate 120 RPM Extruder Speed 150 RPM Temperature 55 C Feed Rate 15 kg/hour Extruder Speed 400 RPM Temperature 40 C Mixer Speed 750 RPM Chopper Speed 1500 RPM Temperature 25 C Ingredients Percentage Comments Acetaminophen Various binders 4.00 Microcrystalline cellulose q.s. Fumed Silica 0.20 Croscarmellose sodium 4.00 Magnesium stearate 0.25 Ashland Total Specialty Ingredients * Trademark owned by a third party Intragranular 10% water Extragranular 23

24 Effect of Different Processes on Tablet Strength 4% Binder Process selection: continuous granulation shows advantages over traditional wet granulation for tablet strength Conventional twin-screw extrusion is best Binder selection: HPC shows stronger profiles 24

25 Effect of Different Processes on Granule Morphology Leistritz ZSE18HP ConsiGma T* -1 Glatt HSG Plasdone K-29/32 PVP Klucel EXF HPC Twin-screw extruded (Leistritz) granules have a distinctly different morphology. 25 * Trademark owned by a third party

26 Direct compression HPMC for controlled release High MW (CR grade) HPMC particles are typically fibrous and moderately flowable. New forms with modified morphology Methocel DC2 HPMC Benecel DC PH HPMC Different approaches: More spherical and densified, Methocel DC2 HPMC Surface modification, Benecel DC PH HPMC 26 *Registered trademark Dow Chemical Co.

27 Case study Metformin CR formulations compressed on a production scale press Comparison of standard HPMC CR grade vs HPMC DC Improved weight and content uniformity, improved tablet strength. Parameter Machine Model (Elizabeth Hata) Settings HT-CTX- MS-U Stations 38 Turret Speed (RPM) 30 Feeder Speed (%) 50 Precompression Force (kn) 2 Main Compression Force (kn) 15 Tablet Target Weight (mg)

28 Stable In-Process Force Control Average compression force was recorded every minute 28

29 Lower in-process Weight Variation Formulation with Benecel DC has better flow and smaller weight variability Formulation # 2 Concentration (%) Metformin HCl 50.0 Benecel K100M 49.5 Mg Stearate

30 Better Mechanical Properties Formulations with Benecel DC have higher tablet hardness 30

31 Acknowledgements Professor Mike Repka and graduate students at Ole Miss John Lian ASI Pharma Divya Tewari ASI Pharma Kapish Karan ASI Pharma Brad Beissner ASI Pharma Vivian Bi ASI Pharma Stu Porter ASI pharma Todd Brugel ASI Molecular Science Jenny Titova ASI Process Research 31

32 Thank you! 32