OMICS International Conferences

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1 About OMICS Group OMICS Group is an amalgamation of Open Access Publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology Open Access, OMICS Group publishes 700+ online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also organizes International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions.

2 OMICS International Conferences OMICS International is a pioneer and leading science event organizer, which publishes around 700+ open access journals and conducts over 500 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. OMICS Group has organized conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.

3 Parenteral Drug Nanodispersions : Manufacturing, Characterization and In Vitro/In Vivo Performance Evaluation Panayiotis P. Constantinides, Ph.D Biopharmaceutical & Drug Delivery Consulting, LLC Gurnee, Illinois, USA Parenterals- 2015, August 17-19, 2015, Chicago, IL

4 OUTLINE PART I : Overview of Parenteral Drug Nanodispersions Particle Size Considerations Drug Products on the Market (Doxil and Abraxane ) Engineering and Manufacturing : Impact on Drug Loading and Release Characterization & QbD Aspects PART II : Case Studies 1. Nanoemulsions : Tocosol -Paclitaxel 2. Liposomes, Polymeric Micelles : Phospho-Ibuprofen (NME) ; Solid Lipid Nanoparticles : Phospho-Sulindac (NME) Conclusions and Future Perspectives 8/18/2015 BPDDC LLC 4

5 PART I Overview of Parenteral Nanodispersions Particle Size Considerations Marketed Drug Products Engineering, Processing, Characterization and QbD Aspects 8/18/2015 BPDDC LLC 5

6 Nanodimensions of Drug Delivery Nanoparticles Mattheolabakis, G., Rigas B., and Constantinides, P.P. Nanomedicine (2012) 7: The true nanorange is narrowly defined as the nm particles. Marketed injectable liposomal and albumin-bound nanoparticulate anticancer drug products, as well as oral NanoCrystal drug products are within the submicron range ( nm). 8/18/2015 BPDDC LLC 6

7 Marketed Parenteral Nanoparticulate Drug Products Liposomes Abelcet and Ambisome (Amphotericin B); DaunoXome, (daunorubicin); DOXIL (doxorubicin), Depocyt (cytarabine) ((HSPC, CHOL Albumin-Bound Nanoparticles Abraxane (paclitaxel nanosuspension) The particle size of these nanoparticulate drug products, is in the range of approx nm and thus above the defined nanorange (1-100 nm).. 8/18/2015 BPDDC LLC 7

8 Nanoparticle Properties and Inter-relationships Nanoparticles Morphology Solubility Alterability Bioactivity Surface Chemistry Charge Biocompatibility Size Shape Film Forming Ability Hydrophobicity Deformability Toxicity Dispersed State Stability 8/18/2015 BPDDC LLC 8

9 Bottom-Up Top-Down Nanoparticle Manufacturing Methods BULK Homogenization Energy Milling Cryogenic Approaches Super-Critical Fluid Technologies Spray Freezing into Liquid Ultra-rapid Freezing SOLUTION NANOPARTICLES Growth Precipitation Solvent Evaporation Emulsion-Diffusion 8/18/2015 BPDDC LLC 9

10 Nanoparticle Engineering and Manufacturing and Impact on Drug Loading and Release Nominal drug loading Type (base vs salt) Drug Lipophilicity Functional groups Drug loading Preparation Solvent, ph, Temperature Sequence of adding excipients Loading during or after nanoparticle formation Release (Release medium) Carrier Type of nanoparticle Type of polymer/copolymer (MW, functional groups on polymers, charge) Ratio liquid/solid lipid (SLN) 8/18/2015 BPDDC LLC 10

11 Lipid Polymorphism with Glycerides : Implications for SLN Mehnert, W. and Mӓder, K. (2001) Adv. Drug Del. Rev. 47 : ; Uner, M. (2006) Pharmazie 61 : 380 supercooled melt Low α-modification (less ordered hexagonal form) High Thermodynamic Stability β -modification (orthorhombic perpendicular form) Drug Loading High β-modification (highly ordered triclinic parallel form) Low 8/18/2015 BPDDC LLC 11

12 Methods Used to Monitor Stability of Nanoparticulate Drugs Method Measured Parameter(s) PCS/DLS Particle size and size distribution SEM/TEM/AFM Morphology Laser Doppler Electrophoresis Surface charge/zeta potential XRD/DSC Crystallinity HPLC/FTIR/NMR/MS Chemical Stability 8/18/2015 BPDDC LLC 12

13 In Vitro/Vivo Performance Characterization Nanoparticle QbD Design Manufacturing QbD is increasingly applied to different types of nanoparticles 8/18/2015 BPDDC LLC 13

14 PART II Case Study 1 Nanoemulsions : TOCOSOL-Paclitaxel 8/18/2015 BPDDC LLC 14

15 Nanoemulsions : Characteristics transparent or translucent o/w or w/o droplets with a mean diameter up to 300 nm. kinetically stable unlike microemulsions which are thermodynamically stable. exhibit great stability in suspension due to their small droplet size Ostwald ripening is the primary instability process Can be reduced by the addition of a second less soluble oil phase and/or addition of a strongly adsorbed and water insoluble polymeric surfactant 8/18/2015 BPDDC LLC 15

16 Nanoemulsions: Emulsification Processes High-Energy 1. High pressure homogenization 2. Ultrasound energy Low-Energy 1. Spontaneous 2. Solvent-diffusion 3. Phase inversion temperature (PIT) McClements, D.J. (2011) Soft Matter 7 : /18/2015 BPDDC LLC 16

17 Oil-in-Water Microemulsions vs Nanoemulsions Very Similar Same process for ME and spontaneous selfformation of emulsions Structural and Visual Aspects Formulation Process Decrease in droplet size for ME No effect on NE size Dilution with Water Temperature Variations Can affect the structure and droplet size of ME No immediate effect on NE 8/18/2015 BPDDC LLC 17

18 TOCOSOL Nanoemulsion Manufacturing *Lipophilic drug that is soluble in a tocol (Vit E) Vitamin E Sterile Filtration and Filling Tocophilic* Drug Mix until all tocophilic drug is dissolved Mix oil phase with aqueous phase HP Homogenization ΔT, ΔP TPGS/Poloxamer 407 Unprocessed Rotor Stator mixed 8/18/2015 BPDDC LLC 18

19 Nanoemulsion Stability : TOCOSOL-Paclitaxel Constantinides, P.P. et. al., Pharm. Res. 17, , Paclitaxel Loading : 9 mg/ml TOCOSOL Mean Droplet Diameter or 99% Cumulative Distribution (nm) Relative Volume Volume Distribution: 62 nm Particle Size (nm) [D] m ean 4 C [D] m ean 25 C [D] 99% 4 C [D] 99% 25 C Time (months) Paclitaxel potency and levels of degradants were within specifications throughout the stability study It can be filter-sterilized! Surfactants (TPGS, P407) R O NH O 3' 1' OH O Oil (Vitamin E) Tocophilic Drug (Paclitaxel) 13 AcO HO R= C 6 H 5, MW = 853 Solubility < 50 µg/ml O O OH 4 OAc O 6 O 8/18/2015 BPDDC LLC 19

20 Paclitaxel in Blood and Tumor Tissue P.P. Constantinides, A. Tustian and D.R. Kessler, Adv. Drug Del. Rev. 56 (2004) Single dose administration of 10 mg/kg to B16 MM-bearing mice Blood Tumor TOCOSOL Paclitaxel Taxol TOCOSOL Paclitaxel Taxol AUC Tocosol-P = 2.2 AUC Taxol Concentration (ng/ml) Concentration (ng/g) Time (hr) Time (hr) Enhanced TOCOSOL nanoemulsion uptake by tumors due to EPR effect 8/18/2015 BPDDC LLC 20

21 PART II Case Study 2 Liposomes/Polymeric Micelles - Phospho- Ibuprofen (PI) Solid Lipid Nanoparticles - Phospho- Sulindac (PS) 8/18/2015 BPDDC LLC 21

22 Phospho-Ibuprofen and Phospho-Sulindac (NMEs) Basil Rigas, WO2009/023631, Anti-inflammatory Compounds and Uses Thereof Development by Medicon Pharmaceuticals, Setauket, NY Phospho-Ibuprofen (PI) ester bond Diacetyl Phosphate H 3 C S Butane (spacer) F H 2 C CH 3 O O O P OCH 2 CH 3 Phospho-Sulindac (PS) O OCH 2 CH 3 8/18/2015 BPDDC LLC 22

23 Preparation of Phospho-Ibuprofen Liposomes Soy PC, DSPE-PEG, Phospho-Ibuprofen Drug - Lipid Mixture Compounding Chloroform Solvent Removal Thin Lipid Film Formation PBS Vortexing + Brief Sonication Hydration (MLV) P-I Liposomes Refrigerated under argon and tested within 1 month after preparation Polycarbonate membranes 0.4 and 0.2 µm pore size P-I Extrusion Down Sizing Dialysis Free Drug Removal Nie, T. et al; (2012) Br. J. Pharmacol.166: /18/2015 BPDDC LLC 23

24 Preparation of Phospho-Ibuprofen Polymeric Micelles Phospho-Ibuprofen and PEO-b-PLA in acetone Drug - Polymer Mixture Compounding PBS Acetone Removal Dialysis Free Drug and Traces of Acetone Removal P-I Polymeric Micelles P-I Refrigerated under argon and tested within 1 month after preparation Nie, T. et al; (2012) Br. J. Pharmacol. 166: /18/2015 BPDDC LLC 24

25 Ibuprofen vs Phospho-Ibuprofen (MDC-917) : Physical Properties and Cytotoxicity Nie, T. et al; (2012) Br. J. Pharmacol. 166: MDC : Medicon Pharmaceuticals Size : 209 ± 16 nm Soy PC + DSPE-PEG Size : 78 ± 8 nm PEO-b-PLA diblock copolymer Z-potential : ± 2.6 mv P-I Z-potential : -6.2 ± 0.6 mv Property Ibuprofen Phospho- Ibuprofen (P-I) LIPOSOMES MICELLES 200 nm 50 nm Partition coefficient (log P) IC 50, µm, range (HT29,HCT116, SW480 colon cancer cell lines) 748-1, Cell uptake, nmol/mg protein /18/2015 BPDDC LLC 25

26 In Vitro Cytotoxicity of P-I (MDC-917) Against Colon Cancer Cell Lines Nie, T. et al; (2012) Br. J. Pharmacol. 166: A. Empty Nanocarriers B. Nanocarrier-drug vs Free Drug Mean ± SD (n=3) 200 Free P-I B IC 50, µm 24- hr Mic P-I Lip P-I 0 SW480 HCT116 HT-29 8/18/2015 BPDDC LLC 26

27 Tumor weight, g Antitumor Activity of Liposomal P-I (MDC-917) in Human Colon Cancer (SW 840)-Bearing Mice Nie, T. et al; (2012) Br. J. Pharmacol. 166: Tumor Volume, mm #Dose : 100 mg/kg/day i.p. Control P-I # # Liposomal P-I # (Mean ± SEM, n=20) # # Treatment, days 0.0 Vehicle control P-I Liposomal P-I 8/18/2015 BPDDC LLC 27

28 Preparation of the SLN-PS by Emulsion/Evaporation Zhu et al; Pharm Res (2012) 29 : PS : Phospho-Sulindac *Myrj 59 dissolved in water heated to 75 C under constant stirring at 700 rpm Stearic acid + lecithin + PS dissolved in chloroform The organic phase was gently injected into the aqueous phase with a syringe *PEG-100 Stearate Stirring for 2.5 h at 1,000 rpm o/w emulsion ice-cold water Stirring continued for another 2 h at 1,000 rpm Centrifugation at 7,200 g for 1 h, the supernatant was removed and the pellet was washed twice with deionized water followed by centrifugation. The final pellet was re-suspended in deionized water, frozen at 20 C overnight and freeze-dried. 8/18/2015 BPDDC LLC 28

29 SLN-PS In Vitro Characterization Zhu et al; Pharm Res (2012) 29 : TEM (cell culture medium) SLN mean D : 55 nm A549 : NSCLC cells (wild type) ; H510 : SCLC cells (mutant) 8/18/2015 BPDDC LLC 29

30 A549 Xenografts Inhibitory Effect and In Vivo Immunostating Zhu et al; Pharm Res (2012) 29 : Tumor Growth Inhibition Induction of oxidative stress tissue sections of A549 xenograft Quantification of cell apoptosis Tumor Targeting Mitochondria Targeting A549 : NSCLC cells ; urinary F2-isoprostane : oxidative stress marker 8/18/2015 BPDDC LLC 30

31 Conclusions and Future Perspectives Parenteral nanodispersions such as liposomes, nanoemulsions, polymeric micelles, and solid lipid nanoparticles: Constitute enabled formulations of approved drugs or NMEs with liposomal and nanosuspension drug products on the market (Doxil and Abraxane ) Recent advances with these drug nanocarriers include: Improvements in manufacturing and characterization methods, drug product quality and performance. At least same efficacy and better tolerance than the earlier systems. Enhanced drug loading/release and targeting Drivers for future growth and commercialization include : funding, patent landscape better understanding of stability issues, particularly with parenteral nanosuspensions and solid lipid nanoparticles ongoing need for novel safe drugs and therapies 8/18/2015 BPDDC LLC 31

32 Acknowledgements Liposomes/Polymeric Micelles Phospho-Ibuprofen (P-I) Solid Lipid Nanoparticles Phospho-Sulindac (P-S) Dr. Basil Rigas and laboratory staff, Stony Brook University, Medical School, Division of Cancer Prevention and Medicon Pharmaceuticals, Setauket, NY 8/18/2015 BPDDC LLC 32

33 Thank You! IVIV Performance Drug Product Quality Formulation and Process Parenteral Drug Nanodispersions 8/18/2015 BPDDC LLC 33

34 Let us meet again.. We welcome you all to our future conferences of OMICS International 2 nd International Conference and Expo on Parenterals and Injectables On October 24-26, 2016 at Istanbul, Turkey