ORALLY INHALED & NASAL DRUG PRODUCTS: INNOVATIONS FROM MAJOR DELIVERY SYSTEM DEVELOPERS www.ondrugdelivery.com 00349_GF_OnDrugDelivery349_GF_OnDrugDelivery PulmonaryPulmonary NasalNasal NovemberNovember 2010.indd2010.indd 1 330/11/100/11/10 111:32:331:32:33 “Orally Inhaled & Nasal Drug Products: Innovations from Major Delivery CONTENTS System Developers” This edition is one in the ONdrugDelivery series of pub- Innovation in Drug Delivery by Inhalation lications from Frederick Furness Publishing. Each issue focuses on a specific topic within the field of drug deliv- Andrea Leone-Bay, Vice-President, Pharmaceutical ery, and is supported by industry leaders in that field. Development, Dr Robert Baughman, Vice-President, Clinical Pharmacology & Bioanalytics, Mr Chad EDITORIAL CALENDAR 2011: Smutney, Senior Director, Device Technology, February: Prefilled Syringes Mr Joseph Kocinsky, Senior Vice-President, March: Oral Drug Delivery & Advanced Excipients Pharmaceutical Technology Development April: Pulmonary & Nasal Drug Delivery (OINDP) MannKind Corporation 4-7 May: Injectable Drug Delivery (Devices Focus) June: Injectable Drug Delivery (Formulations Focus) Current Innovations in Dry Powder Inhalers September: Prefilled Syringes Richard Sitz, Technical Manager, DPI Technology October: Oral Drug Delivery Platform Leader November: Pulmonary & Nasal Drug Delivery (OINDP) 3M Drug Delivery Systems 10-12 December: Delivering Biologics (Proteins, Peptides & Nucleotides) Pulmonary Delivery & Dry-Powder Inhalers: SUBSCRIPTIONS: Advances in Hard-Capsule Technology To arrange your FREE subscription (pdf or print) to Mr Brian Jones, Scientific Advisor, Mr Fernando Díez, ONdrugDelivery, contact: Business Development Manager Guy Furness, Publisher Qualicaps Europe, S.A.U. 16-18 T: +44 (0) 1273 78 24 24 E: [email protected] Pulsating Aerosols for Sinus Drug Delivery: SPONSORSHIP/ADVERTISING: New Treatment Options & Perspectives in To find out more about how your company can become Chronic Rhinosinusitis a participant in ONdrugDelivery, contact: Dr Manfred Keller, Executive Vice-President and CSO, Guy Furness, Publisher Uwe Schuschnig, Senior Manager, Aerosol T: +44 (0) 1273 78 24 24 Characterisation, Dr Winfried Moeller, Senior E: [email protected] Scientist, iLBD PARI Pharma GmbH 20-24 MAILING ADDRESS: Frederick Furness Publishing 48, Albany Villas, Hove, East Sussex, BN3 2RW Simulating Delivery of Pulmonary United Kingdom (and Intranasal) Aerosolised Drugs Dr Siladitya Ray Chaudhuri, Senior Scientist, Dr Viera PRODUCTION/DESIGN: Lukacova, Team Leader, Simulation Technologies Mark Frost Simulations Plus, Inc 26-30 www.frostmark.co.uk Modifying MDI Canister Surfaces to Improve “Orally Inhaled & Nasal Drug Products: Innovations Drug Stability & Drug Delivery from Major Delivery System Developers” is published Mr Richard Turner, Business Development Director by Frederick Furness Publishing. Presspart Manufacturing Ltd 32-34 Copyright © 2010 Frederick Furness Publishing. All rights reserved The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication. 2 www.ondrugdelivery.com Copyright © 2010 Frederick Furness Publishing 00349_GF_OnDrugDelivery349_GF_OnDrugDelivery PulmonaryPulmonary NasalNasal NovemberNovember 2010.indd2010.indd 2 330/11/100/11/10 111:32:371:32:37 BREATHE EASY with a cGMP Laboratory Market Leader In a world where many labs can make you feel Our flagship lab in Middleton, Wis., is one like a number, personal service is welcome. of the largest analytical testing facilities for We adapt to your needs, pulmonary inhalation and customize your testing Another breath of fresh air… nasal products. Our recently and reporting and dedicate PPD is a market leader in opened facility in Athlone, a team to work with you inhaled and intranasal Ireland also has full inhalation personally throughout products testing. testing capabilities. your project. When you trust your With PPD, you can count on our excellent respiratory product analysis to the experts regulatory record, multiple state-of-the-art at PPD’s cGMP labs, you can breathe a sigh facilities in the U.S. and Europe and swift ’ of relief, knowing that your testing will be automation to deliver accurate, reliable data. completed on budget and right on time. Welcome to PPD’s cGMP Laboratories. For more information, call Nick Maraveyias at +1 910 815 3476 or visit us at [email protected] DISCOVERY/PRECLINICAL > PHASE I > PHASE II-IIIb > POST-APPROVAL > LABS © 2010 Pharmaceutical Product Development, Inc. All rights reserved. 00349_GF_OnDrugDelivery349_GF_OnDrugDelivery PulmonaryPulmonary NasalNasal NovemberNovember 2010.indd2010.indd 3 330/11/100/11/10 111:32:381:32:38 INNOVATION IN DRUG DELIVERY BY INHALATION In this article, Andrea Leone-Bay, PhD, Vice-President, Pharmaceutical Development, Robert Baughman, PharmD, PhD, Vice-President, Clinical Pharmacology & Bioanalytics, Chad Smutney, Senior Director, Device Technology, and Joseph Kocinsky, Senior Vice-President, Pharmaceutical Technology Development, all of MannKind Corporation, describe the powder fomulation technologies and delivery devices the company is developing for drug, including insulin, delivery to the systemic circulation via the lungs. Historically, the lung has been viewed as a and offers the additional advantage of providing filtering organ not amenable for drug delivery. unique pharmacokinetics characterised by ultra- However, the lung provides a large absorptive rapid drug absorption. surface area, a thin alveo-capillary membrane, and a large vascular bed through which the FORMULATION TECHNOLOGY entire cardiac output flows with every heart beat. Additionally drugs administered by the MannKind’s dry-powder formulations pulmonary route avoid the challenges associated are based on the novel excipient, fumaryl with transiting the gastro-intestinal tract. diketopiperazine (FDKP), shown in Figure 1. Given these characteristics and the desire FDKP is a substituted diketopiperazine that for rapidly absorbed drug products provided forms the Technosphere particle matrix and is in patient-friendly formats, MannKind the primary component of Technosphere dry- Corporation has developed an inhaled drug powder formulations. The particles can be either delivery technology based on dry-powder crystalline or amorphous (Figure 2). Crystalline formulations delivered through discrete, breath- particles are prepared by a controlled, pH-induced powered inhalers. Additionally, MannKind’s crystallisation process in which FDKP nanocrystals Andrea Leone-Bay 1-6 proprietary inert excipient, FDKP (fumaryl self-assemble into microparticles. Vice-President, Pharmaceutical diketopiperazine), the primary component of A crystalline Technosphere particle can Development these Technosphere® dry-powder formulations, be envisioned as a three-dimensional sphere T: +1 203 796 3421 F: +1 203 798 7740 has the ability to deliver drugs in a cost-effective constructed from a deck of playing cards. Each E: [email protected] manner that is well-tolerated by patients. card represents an FDKP nanocrystal and the MannKind has utilised this drug delivery sphere constructed from the cards represents Dr Robert Baughman technology during the development of a Technosphere particle. The back and front Vice-President, Clinical Pharmacology & Bioanalytics Technosphere Insulin (Afrezza®), an innovative faces of the cards provide the sphere with a and patient-friendly orally inhaled insulin, to large surface area. The spaces between the cards Mr Chad Smutney establish a formulation/device/development provide the sphere with a high internal porosity Senior Director, Device Technology system with the potential to change the paradigm resulting in low density and suitable aerodynamic Mr Joseph Kocinsky for inhaled drug delivery. properties for deposition in the distal airways. Senior Vice-President, Going forward, systemic delivery by These crystals provide a large surface area Pharmaceutical Technology inhalation will have a dramatic impact on onto which drugs can be adsorbed to make an Development the market as more active agents are shown inhalation powder.7 Amorphous particles can to benefit from this route of administration. be formed from a salt of FDKP and the drug. MannKind Corporation However, the real impact will be realised Such particles are a homogenous composite of One Casper Street when patients are given the opportunity to the FDKP salt and drug. Once the crystalline Danbury, CT 06810 self-administer therapies in easy-to-use, or amorphous Technosphere particles are United States patient-friendly delivery systems. MannKind’s formed, they are not processed further. Particle www.mannkindcorp.com technology system meets all these requirements size is fixed during particle formation (either 4 www.ondrugdelivery.com Copyright © 2010 Frederick Furness Publishing 0349_GF_OnDrugDelivery Pulmonary Nasal November 2010.indd 4 30/11/10 11:32:38 it must maximally harness the energy contained in an inhalation to lift and separate individual particles, but not impart too great a velocity onto any one. Particles with high momentum cannot change direction quickly enough to avoid inertial impaction in the conducting airways and may never reach the distal lung