Designing amorphous dispersion formulations for poorly soluble drugs Ian Yates – Product Development Lead, Lonza Bend Tyler Clikeman – Senior Scientist, Product Development, Lonza Bend WEBINAR | May 23rd, 2019
Presentation Outline • Lonza D Dosage F Forms and Deliver ery S System ems (DFDS) Intro • Proble blem s statement de defini nitio ion a and f nd formulation s selection • Amorpho hous us s spray-drie ied di d dispe persio ion formul ulatio ion des esign • Case s e studies es • Physical stability • Chemical stability • Correlating in vitro performance testing to in vivo data Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019
Lonza DFDS Business Model Feasibility Studies Des esig ign Small / Lab-Scale (non-GMP) Dev evel elop Clinical Scale Manufacture Drug S Substance Drug s substances Drug P Product Drug P Products Commercial Scale Inte termed ediates tes Inte termed ediates tes Commercial Manufacture Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 3
Specialized Focus Areas Design gn Develop lop Manufacture e Drug S Substance Drug P Product Ea Early –stage Clinical Clinical T Trial Comme mmercial Concepts ts Trial Mat aterial als Materials and I Inte termediate tes Supply • Customized • Addr • Mod ed A API Dev evel elopmen ent ddressi essing B Bioavailabi bility odif ifying P Pharmacokin okinetics Challeng nges es • High • Multi ghly P Pote tent A t API & Drug P g Products ts ti-particulate F e Formulations ns • Particle E Eng ngineer eering Pr Prod oduct Opt ptions ns Drug Product Soft Gelatin Tablets – IR, Osmotic, Powder Multi-particulate Liquid-filled API / HAPI Intermediate Capsules Matrix, Orally Dissolving Filled Capsules Hard Capsules Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 4
Problem Statement Definition and Formulation Selection Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019
Biopharmaceutical classification system 70-80% of drugs in pharmaceutical pipeline are low solubility IIA D Dissolution Rate L e Limited ed Our BA enhancement toolkit is geared towards IIB S Solubility addressing BCS II and IV compound challenges Limited Butler, J., Dressman, J. J. Pharm. Sci., 2010 Depth in all enabling technologies used in addressing either BCS IIA, IIB, and IV compounds • phase-appropriate equipment • extensive track record • predictive modeling & tools for tech selection 2008;7:255–270 Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 6
Problem statement definition guides technology choice Goal is to efficiently arrive at product development with enabling approach SDD LIPIDIC NXSTAL HME Product C t Concept Technolog ogy & y & For ormula latio ion Mole olecula lar P Prop opertie ies Problem em S Statem emen ent Predictions In v vit itro, in s silic lico, & i in v viv ivo testin ing Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 7
Many Enabling Technologies Are Available for Bioavailability Enhancement Solv lvation ion API S I Sel electi tion Cr Crystal F Form rm Size R e Reducti tion Amorphous • Solid dispersions • Polymorphs • Molecular • Cosolvents • Micronization modification • SDD • Cocrystals • Surfactants • Sub-micron crystals (100 to • Pro-drugs • HME • Salts • Cyclodextrins 800 nm) • Lyophiles • Nanocrystals (<100 nm) • Lipids: • Drug/polymer • Oils nanoparticles • SEDDS/SMEDDS Route te of A Admin • Layered beads, • Solid lipid pellets • Oral nanoadsorbates • Solid lipid • Parenteral • Pure amorphous drug nanoparticles • Pulmonary Lonza Bend Technologies in BA Enhancement Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 8
Important Considerations for Pre-formulation Assessment Solu lubilit ility 1. 1. Crys ystal alline A Aqueou ous Aqueous S Solu lubili ility C Challe llenge 2. 2. Amorphous A Aqueous Pharmac macokinetics 3. Crystallin 3. lline O Organic ic 1. 1. Lipophilic ilicit ity/ y/Mic icelle lle p par artit itio ionin ing 1. 1. Absolute B BA 2. 2. Melt ltin ing p poin int/Crystal l l lattic ice 2. BA dose d 2. dependence energy ( (i.e .e. “ . “bri rick ck d dust”) 3. Food e 3. eff ffect 4. 4. Gastr tric p pH H effect Physic ical S l Stabil ilit ity Targ rget P Pro roduct P Pro rofile 1. 1. Ther ermal P Proper erties es 1. Clin 1. inic ical P l Phas ase (e.g .g. T Tm, T Tc, c, Tg Tg) 2. 2. Dose se 2. Wat 2. ater U Uptak ake 3. 3. Dosing F g Frequency 4. In viv 4. ivo mod model ( l (e.g. r rat, dog, m , monkey, , human, e , etc.) c.) Permeabilit ility 1. Molecular 1. lar D Descrip iptor ors Chemic ical S l Stabilit ility (e.g. g. M MW, r rotatable b bonds, 1. 1. Labile f functi tional g groups Metabolis Me lism/ charge s sta tate te) ) 2. 2. Forced d degr gradati tion Ef Efflux 2. 2. Caco co-2 3. 3. Perfu fusion Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 9
Technology Mapping Bioavailability Enhancement Map Fraction Absorbed Classification System Amorphous Dispersion Guidance Map (FACS) Williams et. al. Pharmacol. Rev. , Sugano and Terada, Pharm. Sci. 104:2777- Friesen et. al. Mol. Pharmaceutics, 5:6 65(2013), 315-499 2788, 2015. (2008)1003-1019 Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 10
Three Areas of Focus for Development of an Amorphous Dispersion Performance: • Problem statement identification Early ly D Development Go Goals: • Initial characterization through complementary 1. Learn as much as we can to deliver in vitro tests the best formulation possible in a • Biomodels to test hypotheses time and cost effective manner • Inputs for in vivo results Performance 2. Position program well for late stage • Refinement of in vitro tests development • Phase appropriate Manufact cturability Sta tability ty • • Define solvent system Prediction using thermal Stability Manufacture • properties Define key process parameters • • Phase diagrams Scale-up considerations • • Accelerated stability Enabling technologies for compounds with poor organic solubility Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 11
Amorphous Spray Dried Dispersion Formulation Design Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019
Spray-Dried Dispersion – What Is It? THE HE PROCE CESS THE P PRODU DUCT Pressure Nozzle Nozzle RESULTIN ING G DRYIN YING G FEED ED S SOLUTION FORMU MULATION GA GAS 10 -6 sec 10 Drug is dissolved Homogeneous, stable, with polymer in a amorphous dispersion common organic solvent. Initial Solution Droplet HAMBER BIOAVAI AILAB ABILITY E ENHAN ANCED • Dissolves rapidly G CHA • Solubility increased Hot Drying Gas YING C • Maintains super- saturation Contacts Droplet DRYIN in intestine PXRD AN ANAL ALYSES 900 900 900 SDD 800 800 800 Amorphous SDD Amorphous SDD Intensity (counts) Intensity (counts) Intensity (counts) 700 700 700 10 -2 se 600 600 600 10 sec 500 500 500 Bulk drug 400 400 400 300 300 300 MULTIPLE ORAL AL D DOSAG AGE Skinned Droplet 200 200 200 Bulk Drug Bulk Drug 100 100 100 FORMS FO S 0 0 0 RESULTING S RE SDD 4 4 4 10 10 10 20 20 20 30 30 30 2-Theta - Scale 2-Theta - Scale 2-Theta - Scale • Tablets The resulting powder is a • Capsules homogenous, stable, SEM SEM TEM • Powder in bottle amorphous dispersion ~1 se 1 sec • CR dosage forms suitable for incorporation into oral dosage forms. 30 microns Dried d SDD P DD Particle Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 13
SDD Dissolution Model Several mechanisms Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 14
Problem Statement-specific Bioperformance in vitro Tools Fl Flux ux Dissolu lutio ion Controlle lled T d Trans nsfer Amorph phous us S Solubilit lubility • Amorphous “solubility” • Dissolution rate • Clean measurement of “effective” • Dissolution rate • Precipitation risk • Precipitation rate • Precipitation rate vs. concentration • Polymer selection • Maximum apparent • Able to properly account for emptying rate • Drug/polymer interaction • Gastric precipitation concentration micelle, colloid, and particle • Speciation • “Book-end” for contribution to boundary layer diffusion and dissolution rate formulation performance Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 33
Physical Stability of Spray Dried Dispersions Thermo modyna nami mics Kinet netics cs Expe perienc ence Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 16
Case Study #1: Modeling Physical Stability with a Chemically Stable SDD Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019
SDD characteristics Low drug loading SDD: 15/85 API/HPMCAS-M • Performance Balance of manufacturability, performance, and • stability required accepting a small amount of crystallization over time Stability Manufacture Modeling showed that we could minimize • physical instability with packaging and storage Yates Clikeman | Pharmaceutical Technology Webcast | May 23rd, 2019 18
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