Nanotechnologie vom Konzept zur Anwendung

Transcription

1 Nanotechnologie vom Konzept zur Anwendung Johannes G. Khinast Institut für Prozess und Partikeltechnik Research Center Pharmaceutical Engineering TU Graz 31.Jänner 2014 K1 Competence Center Initiated by the Federal Ministry of Transport, Innovation & Technology (MMVIT) and the Federal Ministry of Economics & Labour (BMWA). Funded by FFG, Land Steiermark and Steirische Wirtschaftsförderung (SFG).

2 Demographische Entwicklung Beispiel Deutschland men women

3 Zahl der Neuzugelassenen APIs Annualized Number of Drugs Approved by FDA Grey: small-molecule drugs (NMEs). Yellow: biologics (BLAs)

4 Neue Wirkstoffe kommen auf den Markt Annualized Number of Orphan Drugs Approved o Numbers for 2012 include drugs for anthrax poisoning, Gaucher s disease, multiple myeloma and cystic fibrosis Source: FDA

5 Beispiele von Durchbrüchen Glybera treatment for enzyme deficiency leading to pancreatitis approved 2012 Vedolizumab, MAB for treatment of Crohns disease, expected to be approved 2013 Ipilimumab for treatment of melanoma Approved 2012 Bosutinib, tyrosine kinase inhibitor for chronic myelogenous leukemia, Approved for non-hodking Lymphoma in 2012 Source: Internet

6 Personalisierte Medizin Drugs that are delivered in a personalized mode (e.g., based on weight, age, life style) = invididualized medicine, patient-centric drug design Drugs that focus only on highly specialized patient population based on genetic markers (Example: Herceptin, Gleevec)

7 Sequenzierungskosten Year: Cost: $3 billion $300 million $20 million $2 million $5,000 $1,000 Source: Internet

8 Pharmakogenomik How an individual s genetic inheritance affects the body s response to drugs More powerful medicines Better, safer drugs appropriately matched to patients More accurate drug dosages Advanced screening for disease Better vaccines Decrease in overall health care costs Improvements in drug discovery & approval process

9 Nanomedizin..Das Konzept o Nanomedicine at early stage but will have revolutionary impact o Improves drug efficacy, bioavailability and dose-response o Better targeting ability o Ideal for personalized medicine o Improved safety compared to conventional medicines o Most exciting concept in nanomedical research: design and development of multifunctional nanoparticle complexes that can simultaneously deliver diagnostic and therapeutic agents to targeted sites Poirot-Mazères I. Legal aspects of the risks raised by nanotechnologies in the field of medicine. J Int Bioethique 2011 Ferrari M., Nature Rev Cancer 2005; Ventola C. Nanomedicine Part I: emerging concepts, 2012

10 Nanoprodukte am Markt First generation nanomedicines (marketed nanomedicines and nano-imaging agents) e.g., Doxil,Cimzia, Abraxane (i.v. suspensions), Rapamune, Emend, Tricor (nanocrystalls) Liposomes Polymeric nanosphere Polymeric nanocapsule Polymeric micelles Phospholipid bilayer Aqueous core Chains (e.g., PEG) Targeting ligand Polymeric matrix Chains (e.g., PEG) Targeting ligand Polymeric matrix Chains (e.g., PEG) Targeting ligand Amphiphilic polymer Targeting ligand

11 Current Status: FDA-Approved Nanomedicines Trade Name Abraxane Examples for FDA Approved Agents Utilizing Nanomedicine Active Ingredient Indication Manufacturer Approval Formulation Albumin proteinbound paclitaxel Metastatic breast cancer Celgene 2005 Injection Alimta Pemetrexed Nonsquamous NSCLC, malignant pleurl mesothelioma Cimzia Doxil Mircera Pegylated ab fragmnet of a humanized anti- TNF alpha antibody Pegylated stabilized liposomal Doxorubicin Metoxy-PEGepoetin beta Crohn s disease, rheumatoid arthritis AIDS related Karposi sarcoma, ovarian cancer Symptomatic anemia Lilly 2004 Injection UCB 2008 Injection Janssen 1995 Injection Hoffman La Roche 2007 Injection Tricor Fenofibrate Hypercholesterolemia Abbot 2004 Tablet Emend Aprepitant nanocrystalls Chemotherapeutic-related nausea and vomiting Merck 2003 Tablet Ventola C., P&T, The Nanomedicine Revolution, 2012, 37

12 Nanoprodukte in klinischen Studien Second generation nanomedicines (nanomedicines and nano-imaging agents in clinical development): Nano-cancer therapies, e.g., Paxceed (phase III), ThermoDox (phase III)

13 Nanomaterialien für neue Nanomedikamente Third generation nanomedicines (nanomedicines and nano-imaging agents).that may enter clinical development Duncan R., Gaspar R., Nanomedicine(s) under the Microscope, Molecular Pharmaceutics, 2011

14 Nanomedizin - Herausforderungen Safety and toxicity aspects (also including long-term toxicity and immunogenicity) Data regarding pharmacokinetics and pharmacodynamics are lacking No existing testing criteria for nanopharmaceuticals (also enormous challenge for FDA-top priority concern) Development of manufacturing processes Integration of risk management and quality management systems, statistical methods and PAT

15 Nanomedikamente = Komplexe Produkte iphone: Nanodrug:

16 Kooperation mit Prof. Eva Roblegg, Institut für Pharmazeutische Wissenschaften, Uni Graz Beispiel unserer Arbeit: Nano-Extrusion (NanEx) Principle: atmospheric degassing vacuum STABLE SOLID NANODISPERSION Nano-suspension added to polymer matrix Mixing, melting & extrusion in one step Solvent removed via devolatilization Potential for continuous manufacturing Ideal for retarded or delayed release forms Ideal for BCS II and IV that have a high T m or are thermally sensitive High drug loadings small pills

17 Schneckendesign Modular screw design allows individual configuration: conveying elements kneading blocks left handed elements specific mixing elements Cross section profile leads to self cleaning screws:

18 SPH Methode zur Simulation LIGGGHTS: DEM DEM-FVM SPH DEM Quarterly Meeting A3.13: Simulation , Graz, Page 18 (taken from:

19 CAD Geometrie Geometry generated with 3D-CAD software: export *.STEP file ( Standard for the Exchange of Product model data ) generation of tetrahedra mesh (*.vtk) (mesh generator gmsh - freely available) Quarterly Meeting A3.13: Simulation , Graz, Page 19

20 Simulationsvideo Nanopartikelextrusion Mischverhalten CU

21 Vielen Dank!