February 2006 Vol 6 No 2 IN THIS ISSUE
INTERVIEW WITH VENTAIRA’S PRESIDENT & CEO LESLIE J. WILLIAMS GIPET Technology 40 Thomas W. Leonard, PhD Edel O’Toole Fiona Brennan, PhD David J. Brayden, PhD pH-Independent Release 53 Munsih Kumar, MPharm Amit Chivate, MPharm S.S. Poddar, PhD Manufacturing Adhesives 76 Katherine L. Ulman Irena Ziec David J. Neun, PhD A Decade in Review 22 Debra Bingham Chris Robinson, PhD Cardinal’s Capabilities 60 Thomas Stuart The science & business of specialty pharma, biotechnology, and drug delivery Micellar Craig Stephen Caroline Nanoparticles 72 Dees, PhD Bruner, MBA M. Corniello Raul Singhvi, ScD Revisiting Silicone Quick-Dissolve Intralesional Pressure-Sensitive Strips: From Delivery of Adhesives Versus Concept to Cancer Treatment Tacky Gels Commercialization www.drugdeliverytech.com NO BARRIERS.
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^ÊÎ ÊÓääÈÊ ÇäÓääÈ{nÇx February 2006 Vol 6 No 2 PUBLISHER/PRESIDENT Ralph Vitaro EXECUTIVE EDITORIAL DIRECTOR Dan Marino, MSc [email protected] CREATIVE DIRECTOR Mark Lafortezza CONTROLLER Debbie Carrillo CONTRIBUTING EDITORS Cindy H. Dubin Guy Furness TECHNICAL OPERATIONS Mark Newland EDITORIAL SUPPORT Nicholas D. Vitaro ADMINISTRATIVE SUPPORT Kathleen Kenny
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All editorial submissions are handled with reasonable care, but the publishers assume no responsibility for the safety of artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but publishers cannot accept responsibility for the accuracy of information supplied herein or for any opinion expressed. Drug Delivery Technology (ISSN 1537-2898) is published 10 times in 2006, January, February, March, April, May, June, July/August, September, October, and November/December by Drug Delivery Technology LLC, 219 Changebridge Road, Montville NJ 07045. Subscription rates: $99.00 for 1 year in the United States, Canada, and Mexico. $153.00 for 1 year outside the United States, Canada, and Mexico. All subscriptions are payable in US funds, drawn on US banks. Send payment to: Drug Delivery Technology LLC subscription Department, 219 Changebridge Road, Montville NJ 07045. Single copies (prepaid) $15.00, US, Canada, and Mexico; $24.00 in all other countries. Add $5.00 per order for shipping and handling. Periodicals Postage Paid at Montville, NJ 07045-9998 and additional mailing offices. Postmaster: please send address changes to Drug Delivery Technology, 219 Changebridge Road, Montville NJ 07045. All rights reserved under the U.S., International and Pan-American Copyright Conventions. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including by Drug Delivery Technology Drug Delivery Technology photocopy, recording, or information storage and retrieval system, without written permission from the publisher. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Drug Delivery Technology LLC for libraries and other users registered with the Copywrite Clearance, 222 4 Rosewood Drive, Danvers, MA 01923; phone: (978) 750-8400, fax: (978) 750-4470. First in Iontophoresis . . .
Trans-scleral The Ocuphor® delivery system dispenses medication to difficult to reach areas of the eye
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Iontophoresis Applications Research and Development •Transdermal •Prototype design • Ocular • Radio-labeled material handling • Systemic • Clinical and regulatory • Local • In vitro and in vivo drug screening Expertise Manufacturing • Electrical and mechanical engineering • Flexible and efficient processes • Analytical chemistry • State of the art automated equipment • Biological sciences • Compliant with FDA QSR and ISO 13485 • Material sciences Milestones • First commercial iontophoretic product • First NDA approved for an iontophoretic system • Substantial U.S. and foreign patents and others pending
IOMED, Inc. Phone: 801 975 1191 Fax: 801 972 9072 [email protected] www.iomed.com AMEX: IOX 34 Revisiting Intralesional Delivery of Cancer Treatment Craig Dees, PhD, points out that using highly toxic chemotherapy agents have had little success with effects not too dissimilar from using a highly concentrated acid, thus using intralesional delivery with a tumor-specific agent whose effects are confined to diseased cells is significantly advantageous.
40 Promoting the Oral Absorption of Drugs in Humans Using Gastro-Intestinal Permeation Enhancement Technology (GIPET) Thomas W. Leonard, PhD; Edel O’Toole, Fiona Brennan, PhD; and David J. Brayden, PhD, provide an evaluation of the GIPET platform technology with a particular emphasis on data that have been achieved in Phase I human trials.
48 Silicone Pressure-Sensitive Adhesives Versus Tacky Gels Mr. Stephen Bruner and John Freedman discuss that while pressure-sensitive silicone adhesives (PSAs) have typically been considered optimal for transdermal applications, silicone gel technology has emerged as an excellent option.
53 pH-Independent Release From Verapamil Hydrochloride- Coated Tablets Munsih Kumar, MPharm; Amit Chivate, MPharm; and S.S. Poddar, PhD; focus on achieving a pH-independent sustained release of a weakly basic drug, verapamil hydrochloride (VHC), in association with succinic acid (SA) “The discussion and data presented from release-retard polymer-coated tablets. provide transdermal drug delivery 60 Cardinal Health: Improving ol 6 No 2 ol 6 No V system designers with another Quality & Efficiency in Healthcare choice in pressure-sensitive-type, Drug Delivery Executive: Thomas Stuart, President of Oral Technologies for Cardinal Health’s Pharmaceutical silicone-based adhesives. Silicones’ Technologies and Services segment, discusses his ebruary 2006
F company’s drug delivery capabilities and provides his historic healthcare use and drug perspective on the future of drug delivery. solubility make both silicone PSAs and tacky gels good candidates for
Drug Delivery Technology Drug Delivery Technology certain drug delivery applications.” p.48
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ODT CUSTOMIZED RELEASE TASTE MASKING ENHANCED BIOAVAILABILITY 65 Ventaira Pharmaceuticals: Breathing Science & Technology Into Medicine Drug Delivery Executive: Leslie J. Williams, President & CEO of Ventaira Pharmaceuticals, Inc., explains how her company is currently developing its own proprietary inhaled drugs for the treatment of asthma and taking advantage of newly created opportunities for existing or novel drugs that may be more easily delivered via inhalation.
68 Quick-Dissolve Strips: From Concept to Commercialization Ms. Caroline M. Corniello reviews some of the physical attributes needed to design a Quick-Dissolve Strip to ensure consumer acceptance, a different water-soluble film intended to deliver the API vaginally, and taste- masking and mouth-feel techniques used to design caffeine and benzocaine Quick-Dissolve Strips.
72 Micellar Nanoparticles: A New Drug Delivery Platform Rahul Singhvi, ScD, explains the benefits of a nanotechnology-based formulation for transdermal therapeutics, such as the ability to deliver drugs that would otherwise be viewed as unsuitable for parenteral delivery.
76 Designing Quality Into the Manufacture of Adhesives Targeted for Healthcare Applications Katherine L. Ulman, Irena Ziec, and David J. Neun, PhD, explain how a medical adhesives alliance has defined and implemented principles of “quality by design” into manufacturing and distribution operations for producing PSAs targeted for transdermal drug delivery systems and drug-loaded patches. “To gain maximum effectiveness and safety, IN EVERY ISSUE ol 6 No 2 ol 6 No V tumors must be treated with Attorney Review ...... 18 Preparing for Drug Pedigrees an agent that only affects Business Development ...... 22 A Decade in Review: The Evolution of the Drug Delivery Industry
ebruary 2006 diseased tissue. Intralesional F Excipient Update...... 30 delivery of tumor-specific Medical Propellant Manufacturing: A Decade of Leadership External Delivery ...... 82 agent can further potentate Understanding Competition the efficacy and provide an
Drug Delivery Technology Drug Delivery Technology additional margin of safety.” p.34
8
Dan Marino, MSc Executive Editorial Director Drug Delivery Technology
Jack Aurora, PhD John A. Bermingham Matthew D. Burke, PhD Director, Pharmaceutical President & CEO Principal Scientist, Exploratory Pharmaceutics Research & Development Ampad, LLC GlaxoSmithKline Pharmascience, Inc
Sarath Chandar, MBA Mahesh Chaubal, Gary W. Cleary, PhD, Vice President, Global PhD, MS PharmD, MBA Marketing & Commercial Associate Director Development President & CTO SPI Pharma Baxter Healthcare Corium International
Sonya Summerour James N. Czaban, JD John Fraher Clemmons, PhD, MBA, MS Attorney at Law President, North Director, Business Heller Ehrman White & America Development McAuliff, LLPP Eurand MediVas, LLC
Philip Green, PhD Keith Horspool, PhD Ravi Kiron, PhD, MBA Director of Business Director, Research Executive Director, New Development Formulations Technology Assessment & Advanced Drug Delivery Pfizer Global Research & Planning BD Development ALZA Corporation
David C. Klonoff, MD, FACP Uday B. Kompella, PhD James W. McGinity, PhD Clinical Professor of Medicine Associate Professor of Professor of Pharmaceutics - UC San Francisco Pharmaceutics University of Texas Medical Director University of Nebraska at Austin Mills-Peninsula Diabetes Medical Center Research Institute
Nasser Nyamweya, PhD Kinam Park, PhD Philip L. Smith, PhD Technical Service Manager President Investment Manager Rohm America Akina, Inc S.R. One, Limited, GlaxoSmithKline ol 6 No 2 ol 6 No V Ronald L. Smith, PhD Cornell Stamoran Tom Tice, PhD Director of Exploratory VP, Strategy & Business Executive Vice President Biopharmaceutics & Process and Chief Scientific Officer Drug Delivery Cardinal Health, PTS Brookwood Pharmaceuticals Bristol-Myers Squibb ebruary 2006
F Research Institute
James Vaughan Howard S. Wachtler Henry Y. Wu, PhD, MS General Manager President & CEO Associate Director 3M Drug Delivery Systems Actinium Pharmaceuticals Merck Research Laboratories Drug Delivery Technology Drug Delivery Technology
10 EUDRAGIT–P® ower Through Flexibility
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For innovative product opportunities, contact us at Europe: +49-6151-18-4019 USA: (732) 981-5383 Pharma Polymers www.pharma-polymers.com Pfizer’s Exubera Receives Approval From US FDA; Nektar Co-Developed the Inhalers & Formulation
Nektar Therapeutics recently reported that Pfizer, Inc.’s The efficacy and safety profile of Exubera was studied in more than Exubera [insulin human (rDNA origin)] Inhalation Powder has been 2,500 adults with type 1 or type 2 diabetes for an average duration of 20 approved by the US FDA for the treatment of adults with type 1 and months. In clinical trials, many patients using Exubera reported greater type 2 diabetes. Exubera was found in clinical trials to be as effective treatment satisfaction than patients taking insulin by injection. as short-acting insulin injections and to significantly improve blood Significantly more patients who had used both Exubera and insulin sugar control when added to diabetes pills. Exubera, which is expected injections or diabetes pills reported an overall preference for Exubera. to be available for patients by mid-year, is the first inhaled form of In patients with type 2 diabetes, Exubera can be used alone as an insulin and the first insulin option that does not need to be alternative to rapid-acting insulin injections or diabetes pills, or in administered by injection in the US. combination with diabetes pills or longer-acting insulin. In patients Nektar developed the inhalers and the powdered insulin with type 1 diabetes, Exubera will be used in combination with longer- formulation for Exubera in partnership with Pfizer. Pfizer is responsible acting insulin. for marketing, manufacturing, and the clinical development of Exubera. Complications commonly associated with uncontrolled or poorly Nektar provides support in the manufacturing process for Exubera controlled blood sugar levels include heart disease, amputation, insulin and manufactures the inhalation devices. Under the agreement blindness, and kidney failure. Diabetes and its complications are between Nektar and Pfizer, Nektar will receive royalties on all marketed estimated to account for $132 billion in direct and indirect US healthcare products as well as revenue for the manufacture of the powders and the costs annually. Nearly 21 million Americans have diabetes and inhalation devices. approximately 95% of these people have type 2 diabetes. “Today's FDA approval of Exubera marks the beginning of a new Exubera is the result of one of the most rigorous and innovative era for diabetes patients in the US who for the first time have an diabetes development programs. Pfizer has invested in two state-of-the- alternative to injectable insulin therapy to control their blood sugars,” art manufacturing facilities: one of the world's largest insulin plants in said Dr. John Patton, Co-founder and Chief Scientific Officer at Nektar. Frankfurt, Germany, and a highly automated, high-tech production “Exubera would not have been possible without Nektar's innovative facility in Terre Haute, Indiana. scientists and engineers and also our partner, Pfizer, who worked with Exubera is a product of a collaboration between Pfizer and Nektar us and remained committed to our original dream of delivering this Therapeutics. Pfizer recently reached an agreement to acquire the medical breakthrough to patients.” Sanofi-Aventis’ worldwide rights to Exubera. The two companies were As quoted in Pfizer's announcement, “Exubera is a major, first- previously in a worldwide alliance to co-develop, co-promote, and co- of-its-kind, medical breakthrough that marks another critical step manufacture Exubera. forward in the treatment of diabetes, a disease that has taken an Patients should not take Exubera if they smoke or have stopped enormous human and economic toll worldwide,” said Hank McKinnell, smoking less than 6 months prior to starting Exubera treatment. If a Chairman and Chief Executive of Pfizer. “The global incidence of patient starts smoking or resumes smoking, he or she must stop using diabetes is currently at epidemic levels. Millions of patients are not Exubera and see a healthcare provider about a different treatment. achieving or maintaining acceptable blood sugar levels, despite the Exubera may affect lung function, so patients need to have their lungs availability of current therapies. Exubera meets a critical medical tested before starting Exubera, and periodically thereafter, as directed by need by offering a highly effective and needle-free alternative to a healthcare provider. The test involves exhaling into a measuring device. diabetes pills and insulin injections to manage this complicated, Exubera is not recommended for people that have chronic lung disease debilitating disease.” (such as asthma, chronic obstructive pulmonary disease, or emphysema). Exubera is a rapid-acting, powder human insulin that is inhaled Also, Exubera should not be used at all by people with unstable or poorly through the mouth into the lungs prior to eating, using the handheld controlled lung disease. ol 6 No 2 ol 6 No V Exubera Inhaler. The Exubera Inhaler weighs 4 ounces and, when Like all medicines, Exubera can cause side effects. As with all forms closed, is about the size of an eyeglass case. The unique Exubera of insulin, a possible side effect of Exubera is low blood sugar levels. Inhaler produces in its chamber a cloud of insulin powder, which is Some patients have reported a mild cough while taking Exubera, which designed to pass rapidly into the bloodstream to regulate the body's occurred within seconds to minutes after Exubera inhalation. Coughing blood sugar levels. occurred less frequently as patients continued to use Exubera. ebruary 2006 F Quoting Pfizer’s announcement again, “Many people who could Nektar Therapeutics enables high-value, differentiated therapeutics benefit from insulin are fearful of injections, so they delay treatment 5 with its industry-leading drug delivery technologies, expertise, and years or 10 years, placing them at risk for serious complications. Now, manufacturing capabilities. The world's top biotechnology and for the first time, patients can improve blood sugar control with fewer pharmaceutical companies are developing new and better therapeutics or no painful injections,” said Dr. William Cefalu, Exubera investigator using Nektar's advanced technologies and know-how. Nektar also and chief of the division of nutrition and chronic diseases at the develops its own products by applying its drug delivery technologies and Pennington Biomedical Research Center, a campus of the Louisiana its expertise to existing medicines to enhance performance, such as
Drug Delivery Technology Drug Delivery Technology State University System, in Baton Rouge. improving efficacy, safety, and compliance.
12
Supernus Pharmaceuticals Acquires Drug Formulation Business of Shire Laboratories, Inc.
Supernus Pharmaceuticals, Inc., a newly formed “Our decision to acquire SLI’s product formulation and development specialty pharmaceuticals company, recently announced the acquisition business was based on SLI’s success and proven track record in developing of substantially all the assets comprising the product formulation and advanced products, such as Adderall XR”, Carbatrol”, Equetro”, and development business of Shire Laboratories Inc., a subsidiary of Shire OraceaTM utilizing its unique technology platforms and capabilities,” added plc. Founded by former SLI President and CEO Jack A. Khattar, Supernus Mr. Khattar. “We will be applying those same technology platforms and has been funded by New Enterprise Associates (NEA) and OrbiMed capabilities to build our own pipeline of specialty products and to continue Advisors. to support our partners.” “We are looking forward to building a premier specialty “This investment opportunity in what is a proven drug delivery pharmaceuticals company,” said Jack A. Khattar, President & CEO of company and management team is very exciting,” said Jim Barrett, General Supernus. “I am grateful for the support and commitment of a strong Partner of NEA and Chairman of Supernus. “We look forward to working with management team and great employees at SLI. They made this Mr. Khattar and his team to build a leading new pharmaceutical company.” acquisition possible and have been key to the successes achieved at SLI. “We are delighted to partner with the management team and NEA and We are also pleased to be partnering with two of the most prominent be part of developing Supernus into a successful specialty pharmaceuticals venture capital firms in life sciences.” company,” commented Mike Sheffery, General Partner of OrbiMed Advisors Supernus Pharmaceuticals, Inc., is a specialty pharmaceuticals LLC and Board Member of Supernus. company focused on developing products for its own portfolio and in Headquartered in Rockville, Maryland, Supernus Pharmaceuticals, Inc. partnership with other pharmaceutical companies, using its proven and is a specialty pharmaceuticals company that has a portfolio of proven and patented technologies and product development capabilities. Among its patented drug delivery technologies with full product development key technologies are ProScreen” and OptiScreen” for lead selection and capabilities, including production of GMP clinical supplies in its own facility. formulation optimization, Microtrol”, SolutrolTM and EnSoTrol”, its oral Supernus will focus on developing differentiated products for targeted controlled-release technologies, and AvertSM its reduced abuse specialty therapeutic areas on its own and in partnership with other potential technology. pharmaceutical companies.
pSivida Announces Several New Pharma Drug Delivery Evaluation Agreements for US Subsidiary
Global bionanotech company pSivida Limited recently the treatment of chronic, non-infectious uveitis, a sight threatening announced that its wholly owned subsidiary pSivida Inc. (formerly inflammatory eye disease affecting approximately 175,000 people in Control Delivery Systems, Inc.) has recently entered into a number of the US. Retisert is the only FDA-approved back-of-the-eye treatment for new evaluation agreements with various companies, including large uveitis. Bausch & Lomb told investors and analysts in December 2005 global pharmaceutical companies, to evaluate pSivida's proprietary that they believe the future for Retisert is bright. platform technology for their developmental compounds. “We believe these new evaluation agreements come at a time The terms of the new evaluation agreements vary, but are when the ophthalmology market is growing strongly and are a typically 12 months in duration with the costs being born by the reflection of growing interest in pSivida's technologies,” said Mr. Gavin counterparty. With these new agreements, pSivida Limited now has Rezos, MD and CEO of pSivida Limited. “We expect to enter into further agreements for pSivida's drug delivery products in 2006.”
ol 6 No 2 ol 6 No evaluation agreements with 3 of the 5 largest pharmaceutical V companies in the world. pSivida is a global bionanotech company committed to the In December 2005, pSivida completed the acquisition of Control biomedical sector and the development of drug delivery products in Delivery Systems, a private US drug delivery company located in the particular in oncology and ophthalmology. Boston, Massachusetts area. Control Delivery Systems, in collaboration pSivida owns or has the exclusive rights to use the intellectual property pertaining to BrachySil, Medidur, Retisert, and Vitrasert. The ebruary 2006 with Alimera Sciences, initiated a Phase III clinical trial in October F 2005 to study diabetic macular edema (DME) patients treated using its company's IP portfolio consists of 70 patent families, 74 granted Medidur platform technology to deliver fluocinolone acetonide. DME is patents, and over 290 patent applications. pSivida owns the rights to the leading cause of vision loss for Americans under the age of 65 with develop and commercialize a modified form of silicon (porosified or approximately 500,000 treatable cases in the US alone. Medidur for nano-structured silicon) known as BioSilicon, which has applications in DME is an injectable, non-erodible intravitreal device that is drug delivery, wound healing, orthopaedics, and tissue engineering. administered in an office procedure as opposed to a surgical procedure. pSivida has granted an exclusive license to its subsidiary, AION This implant is designed to release a constant amount of drug to the Diagnostics Limited, to develop and commercialize diagnostic products using BioSilicon, and has also granted an exclusive license to its Drug Delivery Technology Drug Delivery Technology back of the eye for a duration of between 18 months and 3 years. Medidur is the next generation product to Retisert, which is subsidiary, pSiNutria Limited, to develop and commercialize food 14 administered in a surgical procedure and licensed to Bausch & Lomb for technology applications using BioSilicon. Boston Scientific & Guidant Announce Signing of Merger Agreement Valued at $27 Billion
Boston Scientific Corporation and Guidant Corporation recently announced that the Board of Directors of Guidant has unanimously approved and entered into the merger agreement provided to Guidant by Boston Scientific on January 17, 2006. Under that agreement, Boston Scientific will acquire all the outstanding shares of Guidant for a combination of cash and stock worth $80 per Guidant share, or approximately $27 billion in aggregate. Prior to entering into this agreement with Boston Scientific, Guidant terminated its merger agreement with Johnson & Johnson. The strategic rationale, business, and growth profile of a combined Boston Scientific/Guidant should be compelling to shareholders of both companies. As a highly diversified company with leading positions in growth markets, Boston Scientific/Guidant will be one of the world's pre-eminent medical device companies, with total revenue in 2006 of nearly $9 billion. “Guidant and Boston Scientific share an entrepreneurial spirit, highly talented employees, strong customer relationships, and an ability to pioneer life-saving therapies for patients around the world,” said Pete Nicholas, Chairman of Boston Scientific. “Shareholders will benefit from the significant upside potential of the combined company, while doctors and their patients will continue to receive the most technologically advanced and highest quality medical devices and therapies. The resources and capabilities of the combined company will allow us to make further investments in our current businesses as well as pursue new revenue opportunities.” “We believe the transaction and the strategic rationale for this combination are in the best interests of our patients, employees, customers, and shareholders - reflecting the full value of our firm,” said Jim Cornelius, Chairman and Chief Executive Officer of Guidant. “The combination of these two companies provides faster, more consistent revenue growth opportunities to shareholders. We want to express our appreciation to our employees who have been dedicated to building this great company, and we all look forward to the future.” “We are excited about combining the talent and experience of Boston Scientific and Guidant employees,” said Jim Tobin, President and Chief Executive Officer of Boston Scientific. “We look forward to working with Guidant to complete the transaction quickly and to creating a global leader in cardiovascular devices.” The transaction is subject to customary closing conditions, including clearances under the Hart-Scott-Rodino Antitrust Improvements Act and the European Union merger control regulation, as well as approval of Boston Scientific and Guidant
shareholders. The transaction is not subject to any financing condition. Boston 2 ol 6 No Scientific expects to complete the transaction by the end of the first quarter of 2006. V As previously announced, Boston Scientific has entered into an agreement with Abbott under which Boston Scientific has agreed to divest Guidant's vascular intervention and endovascular businesses, while agreeing to share rights to Guidant's drug-eluting stent ebruary 2006 program. Under its agreement with Abbott, Boston Scientific will receive $6.4 billion F in cash from Abbott on or around the closing date of the Guidant transaction. This amount consists of $4.1 billion in purchase price for the Guidant assets, a loan of $900 million, and Abbott's agreement to acquire $1.4 billion of Boston Scientific common stock. Boston Scientific and Guidant believe that Boston Scientific's agreement with Abbott will enable Boston Scientific and Guidant to rapidly secure antitrust approvals for the proposed transaction. Drug Delivery Technology Drug Delivery Technology
15 Alkermes & Lilly Announce Agreement to Develop & Commercialize Inhaled Parathyroid Hormone for Osteoporosis
Alkermes, Inc., and Eli Lilly and Company “We look forward to expanding our collaboration with Alkermes recently announced they have signed an agreement to develop and to benefit patients with osteoporosis,” said Patricia A. Martin, commercialize inhaled formulations of parathyroid hormone (PTH). Executive Director of Osteoporosis Products for Lilly. “We believe that The development program will utilize the Alkermes AIR pulmonary the Alkermes technology has the potential to increase compliance and drug delivery system. Lilly's recombinant PTH, Forteo [teriparatide ultimately improve clinical outcomes for patients with osteoporosis.” (rDNA origin) injection], was approved in 2002 by the FDA for the The partnership to develop and commercialize PTH marks the treatment of osteoporosis in postmenopausal women who are at high third collaboration between Alkermes and Lilly to develop medicines risk for bone fracture and to increase bone mass in men with primary based on Alkermes' AIR pulmonary drug delivery technology, which or hypogonadal osteoporosis who are at high risk for fracture. The utilizes a small, easy-to-use inhaler designed to reliably deliver a agreement was signed after completing extensive feasibility work. broad range of doses. In 2000, the companies established an alliance Under the terms of the agreement, Alkermes will receive funding for the development of an inhaled formulation of human growth for product and process development activities and upfront and hormone (hGH), currently in Phase I clinical development. In 2001, milestone payments. Lilly will have exclusive worldwide rights to the companies entered an agreement to develop an inhaled insulin products resulting from the collaboration and will pay Alkermes system that delivers human insulin inhalation powder (known as royalties based on product sales. HIIP). Lilly and Alkermes began Phase III clinical studies with HIIP Alkermes and Lilly will form a joint development team and in July 2005. will share responsibility for executing the overall development Alkermes, Inc., is a pharmaceutical company that develops strategy for inhaled PTH. Alkermes will have responsibility for products based on sophisticated drug delivery technologies to nonclinical development activities, primarily formulation testing enhance therapeutic outcomes in major diseases. The company's lead and device development. Lilly will have responsibility for all commercial product is the first and only long-acting atypical other nonclinical development activities as well as all clinical antipsychotic medication approved for use in schizophrenia. The development and regulatory activities. company's lead proprietary product candidate, VIVITROL (naltrexone “Expanding our partnership with Lilly to include the for extended-release injectable suspension), is being developed as a development and commercialization of parathyroid hormone once-monthly injection for the treatment of alcohol dependence. The provides an opportunity to leverage the experience we have company has a pipeline of extended-release injectable products and gained from our inhaled insulin and human growth hormone pulmonary drug products based on its proprietary technology and collaborations,” stated Richard Pops, CEO of Alkermes. “In addition, expertise. Alkermes' product development strategy is twofold: the we believe this partnership underscores the value of the Alkermes company partners its proprietary technology systems and drug AIR technology system, which is designed to provide patients delivery expertise with several of the world's finest pharmaceutical with a simple method of delivery across a variety of diseases that companies and it also develops novel, proprietary drug candidates may enhance treatment outcomes.” for its own account.
Mylan Laboratories Signs Two Strategic Agreements With ol 6 No 2 ol 6 No V Cephalon to Utilize MTI's Advanced Transdermal Technology
Mylan Laboratories, Inc., recently announced two “This type of collaboration will leverage MTI's state-of-the-art strategic agreements between its subsidiary Mylan Technologies, Inc. technology and expertise and has the potential to allow Mylan ebruary 2006 F (MTI) and Cephalon, Inc., to utilize MTI's innovative transdermal to participate in branded commercial opportunities without technology to address certain pain and central nervous system disorders. additional R&D net costs. These agreements are the latest in Under the terms of the agreements, Mylan and Cephalon will collaborate what we believe will be a series of branded strategic alliances with the intent to create branded transdermal products to develop and and further demonstrate MTI's position as partner of choice for commercialize in exchange for payment of milestones and ongoing transdermal technology.” royalties to Mylan based on net sales of the products. Specific product Mylan Laboratories, Inc., is a leading pharmaceutical company and financial details were not disclosed. with three principal subsidiaries, Mylan Pharmaceuticals, Inc., Mylan “Building strategic alliances of this type for MTI is consistent with Technologies, Inc., and UDL Laboratories, Inc., that develop, license, Drug Delivery Technology Drug Delivery Technology the growth and brand re-entry strategy that we previously outlined,” said manufacture, market, and distribute an extensive line of generic and 16 Robert J. Coury, Mylan's Vice Chairman and Chief Executive Officer. proprietary products. Endo Pharmaceuticals Announces License Agreement With ZARS PHARMASOURCING&SERVICES for Synera, An FDA- AT INTERPHEX2006 Approved Topical Local Anesthetic Patch
Endo Pharmaceuticals Inc., a wholly owned subsidiary of Endo Pharmaceuticals Holdings Inc., recently announced it has signed a license agreement with ZARS Pharma that will give Endo the exclusive North American rights to Synera (lidocaine 70 mg and tetracaine 70 mg) topical patch. Under the terms of the agreement, Endo will pay ZARS an upfront fee of $11 million, with additional payments of up BUILDING PARTNERSHIPS. to approximately $27 million upon achievement of certain commercial milestones. Endo will also pay ZARS undisclosed You can accomplish great things with Build your outsourcing expertise at royalties on net sales of Synera. ZARS is a privately held the right outsourcing partners. Contract INTERPHEX! Get the information you company based in Salt Lake City, Utah, focused on the service providers can help you eliminate need to maximize ROI from both new and development and commercialization of patented technologies bottlenecks. Add new capabilities. Increase existing outsourcing arrangements in the capacity. Gain specialized expertise. Access all-new Outsourcing & Services conference that deliver drugs into and across the skin. cutting-edge technologies. Ensure regulatory track, which includes sessions on supplier Synera is a topical local anesthetic patch for use on compliance. Change fixed costs to variable relationship management, improving sourcing intact skin to provide local dermal analgesia in children and costs. Minimize risk. And get new products relationships, and outsourcing in today’s adults. Approved by the US FDA on June 23, 2005, Synera is onto pharmacy shelves faster. market. expected to become commercially available in the second half At PharmaSourcing & Services at So start building valuable new INTERPHEX™,you can evaluate potential partnerships today! Register online now to of 2006. The safety and efficacy of Synera have been partners for every stage of the pharmaceu- attend PharmaSourcing & Services at demonstrated in a series of clinical trials that included more tical manufacturing process, from contract INTERPHEX2006. For free show admission, than 660 pediatric (aged 3 to 17 years) and adult patients research to process development and scale- visit www.interphex.com/delivery. undergoing superficial dermatological procedures. up, clinical or full-scale manufacturing, “We are pleased to add an innovative treatment, such as validation, testing, packaging, distribution March 21-23, 2006 and more – all under one roof. Jacob K. Javits Convention Center, NY Synera to our growing product portfolio,” said Peter A. You can discuss your requirements with Lankau, Endo's President and Chief Executive Officer. “We major providers like Cardinal Health, DSM believe that Synera is a good strategic fit for Endo, consistent Pharmaceuticals, Alcoa Flexible Packaging, with our objective of expanding our commercial presence in AES Cleanroom Technology, Patheon, Alcan the institutional setting.” Packaging, Lancaster Labs and Washington Group. Learn about small, specialized vendors He noted that Endo will promote Synera through its who provide unique and highly innovative existing 70-person hospital sales force, which currently solutions. And get a clear picture of which promotes DepoDur (morphine sulfate extended-release providers will be the “best fit” for your liposome injection), a novel single-dose, extended-release company’s culture and objectives. injectable formulation of morphine. www.interphex.com/delivery According to published data, children under the age of Sponsored by: Media Supporter: Produced and 15 are hospitalized for an estimated 11.5 million days managed by: annually. These children are routinely subjected to multiple venous access procedures, such as, IV starts, IV changes, and blood draws. Source Code: XDDT ol 6 No 2 ol 6 No Mr. Lankau added that Synera will also be studied for V use with additional procedures, such as pediatric immunization, potentially giving healthcare providers another option to reduce the injection-site pain associated with childhood immunizations. ebruary 2006 Synera has a thin layer of local anesthetic formulation F integrated with an oxygen-activated heating element (Controlled Heat-Assisted Drug Delivery, or CHADD). The heating element enhances the delivery of lidocaine and tetracaine anesthetics into the skin. When removed from the storage pouch, the patch begins to heat, warming the skin after application. Synera has a familiar, adhesive bandage-like
appearance and is applied 20 to 30 minutes prior to Drug Delivery Technology venipuncture, intravenous cannulation, or superficial dermatologic procedure. 17 18 Drug Delivery Technology February 2006 Vol 6 No 2 m agreements onbehalfof drug and clinical trial and other FDA-related e (CPSC). Ms. Martello alsohasextensive Consumer Product SafetyCommission enforcement matters before the as onconsumer product regulation and ma r Federal Trade Commission (FTC) Enforcement Administration (DEA)and r involving drug advertising. She also r and food, including FDA and FTC biotechnology, dietary supplements, (prescription and OTC), medical devices, pertaining topharmaceuticals compliance, and enforcement issues BIOGRAPHY egulation and oversight of drug egularly counsels clients onDrug egulation and enforcement inmatters xperience innegotiating and drafting edical device manufacturers. nu f acturers and distributors, aswell Preparing ForDrugPedigrees FDA regulatory, practice focuses on W He Practice Group of attorney inthe FDA Martello Ms. Kendra A. ashington, DC.Her ller Ehrman LLPin is an D by technologies,electronic pedigree which the Agency anticipates may beaccomplished thatitwantedon thegrounds toprovide timetovoluntarily industry implement postponed. Mostrecently, theFDA stayed theeffective dateuntilDecember1,2006, requirements; however, theeffective dateoftheregulations hasbeenrepeatedly tothetransaction). names andaddressesofallparties (includingthedateoftransaction andthe prior sale,purchase,ortradeof suchdrug distribution, provide thepersonreceiving withastatementidentifyingeach thedrug manufacturer orauthorized distributorofrecord Act requireseachpersonengagedinwholesale distributionofadrug, productsinthechainofdistribution.Specifically, forprescriptiondrug pedigrees the to the pedigree componentsofsuchlegislation. to thepedigree representatives, increasedlicensureorregistration requirements). is limited This article distribution generally (eg, bond orequivalent securityrequirements,designated typically includeadditionalmeasurestoexercise controlsover wholesale drug Additionally,significant. statelegislative counterfeiting aimedatcurbingdrug reforms requirements,Florida’sconsidered pedigree andCalifornia’s aretwo ofthemost take effect untilDecember 1,2006. While otherstateshave implementedand/or however, have theserules beenrepeatedly stayed arenotscheduledto andcurrently (FDA) products; totrackwholesale distributionsofdrug alsopromulgatedrules distributionchain. ofthedrug or someportion The Food andDrug Administration totheendcustomer productfromthemanufacturer requirements thatwilltrackadrug implemented inFloridaandCalifornia. requirements. andthosebeing This columnsummarizesthependingfederalrules, such companiesshouldbeproactively preparingtomeetthependingpedigree wholesalers, manufacturers, and andotherdistributors, impactondrug significant some ofwhich aresettobecomeeffective thisyear, willhave apotentially todetectandpreventof prescriptiondrugs counterfeiting. These requirements, developing requirementsthataimtotracethemovement “pedigree” andownership reach $75billionby 2010. As aresult,federalandstategovernments are D
2007. As the Agency explained in2004,theFDA isworking with stakeholders The FDA promulgatedregulations implementing thesePDMApedigree Marketing passedin1987,requires The PrescriptionDrug Act (PDMA),first To By:
combat drug counterfeiting,manycombat drug stateshave developed “pedigree” the Public salesisprojectedto Interest,thevolume ofcounterfeitdrug States. According torecentstatisticsfromtheCenterforMedicinesin r Ke ug counterfeiting has become a significant problem intheUnited ug counterfeitinghasbecomeasignificant ndr a Martello, Esq. FEDERAL LEGISLATION of such drug, to, beforeeach of suchdrug, w ho isnotthe • • detail: administering ordispensingthe drug. papermust The pedigree orotherperson sale toapharmacy repackager, until final throughacquisition andsalebymanufacturer any wholesaler or fromsale by(ie, prescription)drug, apharmaceutical thatrecordseachdistributionofalegend containing information approvedelectronic form, by ofHealth, theFloridaDepartment documentation relatedtoitssalesofprescriptiondrugs. mustmake available,manufacturer uponrequest,distribution thedistributionofdrug. to further To verify compliance,each repacking orotherwisechangingthecontainer, wrapper, orlabeling as person thatrepackagesaproduct;“repackage”isdefined must comply paperrequirements. withpedigree A repackagerisany record.” Moreover, theFloridastatuteclearly statesthatrepackagers PDMA, thereisnoexemption of for“authorizeddistributors person who paper. receives witha pedigree thedrug Unlike the manufacturer, product, in thewholesale distributionofadrug legislation thatwilltake effect in2006and2007,respectively. haveFlorida andCalifornia separately developed pedigree drug andevaluateproposed rules pedigrees, thefeasibilityofdrug w requirements becomeeffective,regulatory ortake otheraction,as delay theeffective requirements,letthe dateofitspedigree solicit public commentonwhether theFDA shouldcontinueto implementation by December1,2006. The meetingisintendedto regarding thefeasibilityofwidespreadRFID concerns counterfeiting. The meetingnoticeacknowledges continued (RFID)technology asamechanismtocombatdrug identification generally andtoincludevendor displays ofradiofrequency held onFebruary 8-9,2006,todiscussanti-counterfeiting issues productatalltimes. drug by travels rule ensuringthatanelectronicpedigree witha the final resolve many thathave oftheconcerns beenraisedwithrespectto requirementsofthePDMAandobviate thepedigree or help fulfill business. Ifthistechnology iswidely adopted, itisexpected to backtotheoriginalmanufacturer,history asaroutinecourseof includingpriortransaction electronicpedigree, generate adefacto v initiativethrough itscounterfeitdrug widespread, tofacilitate oluntary adoptionoftrackandtracetechnologiesoluntary thatwill ell as other significant issues. ell asothersignificant the drug nameandthemanufacturer’sthe drug name; the amountof drug; asadocumentinwrittenor paper” isdefined A “pedigree Under Floridalaw, effective July 1,2006,eachpersonengaged While theFDA continuestopostponeimplementation ofits Most recently, theFDA announcedapublic meetingtobe FLORIDA STATE REQUIREMENTS must, before distribution of the drug, providemust, beforedistributionofthedrug, the w ho isnotthe • • following means: paper,transaction onapedigree usingoneormoreofthe is requiredtobeprovided totherecipientofdrug. paper then a pedigree thatitdidnotmanufacture, prescription drug alsoengagesinthewholesalemanufacturer distributionofany logisticscontracted third-party provider foramanufacturer. Ifa the distributionpointisowned by orisa themanufacturer whetherand itincludesthedistributionpointformanufacturer NDA/ANDA holdereven isused, thoughacontractmanufacturer includestheactualmanufacturer, thatamanufacturer the clarifies IntheQuestionsand manufactures. Answers document,thestate paperwhenpedigree itsellsordistributesaproductthat required. isnot,however,A manufacturer requiredtoprovide a paperis thenapedigree thatitdidnotmanufacture, a drug engagesinwholesale thatifamanufacturer distributionof clarifies thestate Florida BureauofStatewide Services, Pharmaceutical CD-ROM,via theInternet, card, smart orothersimilardevices. onto paper. may Datainanelectronicpedigree alsobetransmitted andcapablerendered intoareadable ofbeingproduced format, theelectronicrecordmustbeeasilyform, readable oreasily isstoredinelectronic Ifthepedigree paper orelectronicform. • • • • • • • telephone callto theseller; reflected onthe document; invoice or shippingdocumentwiththe sellerorshippingpoint w invoices or orshippingdocuments fromthatmanufacturer incompleteness, orinconsistency ascomparedtoother w seller tothepurchaser. If thismechanismisused, the receipt ofaninvoice orothershippingdocumentfromthe custody of the legend drug. custody ofthelegend drug. email addressforeachwholesaler involved inthechain of the name,address,telephonenumber, and, ifavailable, the papers;and the pedigree thattherecipientwholesaler hasauthenticated a certification number uniquely identifyingthetransaction; an invoice numberorashippingdocumentanother deliveryperson certifying orreceiptofthedrug; includingthenameandaddressofeach shipping information, signature; the nameandaddressofeachowner andhis ofthedrug Wholesale distributorsarerequiredtoauthenticateeach In a“Questionsand Answers” documentreleasedby the Thus, theFloridastatuteallows tobeeitherin thepedigree its lotnumber; andstrength; its dosageform holesaler, and mustrandomly verify theauthenticityof the holesaler mustreview thedocumentforsignsoftampering, 19 Drug Delivery Technology February 2006 Vol 6 No 2 • e-mail communication to the seller; • the business name, address, and, if appropriate, the state • verification of the transaction through a web-based system license number, including California state license number, established by the seller or an independent secure third party; of each owner of the drug, and the drug’s shipping information, including the name and address of each • receipt of a legible and unaltered copy of a previous person certifying to delivery or receipt of the drug; and transaction’s pedigree paper that had been signed under oath at the time of the previous transaction to support the • a certification from a responsible party of the source that transaction to which the pedigree paper relates; or the information in the pedigree is true and accurate. • receipt of a pedigree in electronic form. To date, California has not developed regulations to implement these requirements. The legislation is currently If a pedigree paper cannot be authenticated due to a slated to take effect on January 1, 2007; however, a statutory clerical error, it must corrected by the sender. If it cannot be mechanism exists to extend the implementation date until authenticated for a reason unrelated to a clerical error, or the January 1, 2008, if the California State Board of Pharmacy reason cannot be satisfactorily determined based on a determines that manufacturers or wholesalers require more preliminary investigation, the shipment must be quarantined time to implement electronic technologies to track drug and the state notified within 3 business days. products. It is difficult to predict whether implementation of Wholesale distributors also must annually provide the state these requirements will be stayed, and thus, manufacturers with a written list of all wholesale distributors and should be preparing for such implementation. manufacturers from whom the wholesaler distributor purchases drugs, and notifications of any changes to the list must be made not later than 10 days after any change to the list. A SUMMARY proposed compliance policy to extend the initial enforcement Some significant differences exist between the California date for pedigree papers for generic drugs until January 2007 and Florida requirements previously discussed. While Florida has been released; however, it has not been adopted as of the clearly states that a pedigree can be either paper or electronic, time this column was written, and it is difficult to predict California’s law clearly mandates the use of electronic whether it will ultimately be adopted. The proposal will pedigrees. Additionally, Florida’s pedigree requirements initiate undoubtedly gain support among some drug manufacturers; with the first wholesale distribution of a drug product; on the however, some may seek to implement pedigree papers earlier other hand, California will require manufacturers to initiate the to gain a competitive advantage. pedigree. Finally, returns are not required to have a pedigree in CALIFORNIA STATE REQUIREMENTS Florida, while all changes in ownership, including returns, will require a pedigree in California. At the same time, the FDA is closely monitoring these California’s pedigree legislation is perhaps the most developments, as evidenced by its re-establishment of its comprehensive in that it requires manufacturers to initiate a Counterfeit Drug Task Force and its continued public meetings. drug pedigree, and it requires that all pedigrees be provided in The possibility exists that if state requirements become too electronic form. A pedigree in California must document each stratified and/or manufacturers or distributors appear too slow change in ownership of the drug, beginning with the to implement electronic pedigree systems, the FDA may step in ol 6 No 2 ol 6 No
V manufacturer through to the pharmacy or other person and attempt to create a national standard. Voluntary industry dispensing, furnishing, or administering the drug. Again, unlike efforts may also be forthcoming. Even if a national standard the PDMA, California law does not recognize the concept of does not occur, it is clear that the distribution of prescription “authorized distributors of record.” drugs is changing, and the use of pedigrees is an important
ebruary 2006 A pedigree in California must include: F consideration for all parties in the distribution chain to help • the source of the drug, including the name, address, state protect against drug counterfeiting. license number, and, if available, California state license Companies who may be affected by the pending pedigree number of the source; requirements should already be preparing for compliance. • the quantity of the drug, its dosage form and strength, the Given the complex, and potentially inconsistent requirements date of the transaction, the invoice number, the container of the various pending rules, questions may inevitably arise for size, the number of containers, the expiration dates, and which companies can contact the author for guidance.♦ Drug Delivery Technology Drug Delivery Technology the lot numbers; 20
A Decade in Review: The Evolution of the Drug Delivery Industry By: Debra Bingham and Christopher Robinson, PhD, MBA
BIOGRAPHIES
Ms. Debra Bingham is a Founding he global drug delivery industry has grown Partner of Valeo Partners, a Washington, DC-based consultancy that provides strategic from just under $20 billion in product revenue consulting and business development in 1995 to nearly $70 billion today (Figure 1). services to life science companies in the TT pharmaceutical, biotechnology, medical Drug delivery has gone from a niche business to a well- device, and drug delivery markets. As part of the Valeo team, Ms. Bingham brings established and important segment of the pharmaceutical clients over a decade of specialized industry. It is accepted as an essential life-cycle expertise in the area of drug delivery, specialty pharmaceuticals, and generic management tool and an enabling instrument for many businesses, as well a deep understanding of the key technologies key pharmaceutical products, such as Lupron Depot®, and market play. At Valeo, her primary focus is in helping clients in the areas of business strategy, business development, growth Zyprexa® Zydis®, Wellbutrin XL®, and Duragesic®. While opportunity assessment, and strategic partnering. She also leads Valeo’s strategic partnering offering in affiliation with Stonecroft the market acceptance of drug delivery products has Capital, a DC-based investment bank, which provides full-service faired very well for many technology providers, the changes transactional capabilities from licensing to M&A. Prior to joining Valeo, Ms. Bingham spent the majority of the past 10 years in the pharmaceutical industry as a whole have placed a working in the pharmaceutical industry assisting companies strain on the traditional drug delivery business model. with strategic business assessment and business development. She has authored many drug delivery business articles and Consolidation in the pharmaceutical industry, thinning technology reviews and is a featured speaker at industry trade conferences. She also worked for an international consulting pipelines, and the growth in the generic industry (Figure 2) company and before that held a scientific research position. has greatly impacted drug delivery companies throughout Ms. Bingham is an active member in the Licensing Executive Society, the Controlled Release Society, and the American the past decade. Association of Pharmaceutical Scientists. The traditional drug delivery business model is Dr. Christopher Robinson is a completely reliant on the drug delivery company’s ability Founding Partner of Valeo Partners, a to sign licensing deals for the use of its proprietary Washington, DC- based consultancy that provides strategic consulting and business technology with partner molecules. Success depends on development services to life science companies in the pharmaceutical, the quality of the partner molecule and the partner’s ability ol 6 No 2 ol 6 No V biotechnology, medical device, and drug to adequately market the product. In the mid 1990s, drug delivery markets. At Valeo, Dr. Robinson’s primary focus is in helping clients develop delivery companies began to amass technology, because winning business strategies, generate at the time, it was believed that attracting a large platform innovative product concepts, evaluate
ebruary 2006 market opportunities, and optimize portfolio strategies. He brings deal would be more likely with a wealth of technology F a results-oriented philosophy to traditional strategic consulting, and has extensive experience working with executive options (Table 1). This was not the case. Even with broad management and cross-divisional project teams to turn strategy and varied platform technologies, drug delivery companies into proven results. Prior to joining Valeo, Dr. Robinson was a Management Consultant at a global strategy consultancy focused were not able to produce the expected growth in revenue on product development strategy, business process optimization, through early stage licensing deals. In order to grow and and implementation. He earned his MBA from Cornell University with specialization in venture capital and entrepreneurship and a produce substantial revenues, the companies recognized
Drug Delivery Technology Drug Delivery Technology PhD in Immunology from the University of Florida where he focused on autoimmune disease and genomics. He also holds a the need to make fundamental changes to the “pure play” 22 BS in Molecular Biology from Lehigh University. drug delivery business model. "$© 3ELF )NJECTION 3OLUTIONS "RINGING YOU SOLUTIONS FOR THE HOME CARE MARKET
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"$ -EDICAL 0HARMACEUTICAL 3YSTEMS I 7IESS 0- HTTPWWWFEMALEPATIENTCOMHTMLARCSIGPHARMAARTICLES??ASP "ECTON $RIVE 4HE DUAL CHAMBER CARTRIDGE SHOWN IS A 6ETTER ,YO #ARTRIDGE 6 ,+ &RANKLIN ,AKES .* 6ETTER ,YO #ARTRIDGE IS A TRADEMARK OF 6ETTER 0HARMA "$ AND "$ ,OGO ARE TRADEMARKS OF "ECTON $ICKINSON AND #OMPANY ¥ "$ "$03?MARKETING BDCOM T ABLE 1 development budgets. Just a sampling of the major consolidation that took place throughout the past decade: • Pharmacia AB and The Upjohn Company merger 1995 • Sandoz and Ciba merger 1996 • Glaxo Wellcome and SmithKline Beecham merger 2000 • Pharmacia & Upjohn and Monsanto/Searle merger 2000 • Pfizer and Pharmacia merger 2000 • Pfizer and Warner Lambert merger 2003 • Sanofi-Synthelabo and Aventis merger 2004 • Yamanouchi and Fujisawa merger 2004 FIGURE 1 As with any significant change in the marketplace, there are winners, and there are losers. The consolidation in the industry has created both. The winners include a number of drug delivery companies that have been able to capitalize on the shift by adjusting business strategy in such a way to take advantage of the vacuum that is created in the market as it consolidates. As an example, companies such as Biovail, and Alkermes are successfully transitioning from technology licensing toward product development and marketing. While the consolidation in the pharmaceutical market caused many drug delivery companies heartache, it is what ultimately opened up great opportunity for a number of small savvy companies. ol 6 No 2 ol 6 No V Merged pharmaceutical companies began to divest CONSOLIDATION & smaller or duplicative products, which became THE RISING OPPORTUNITY available for specialty pharma and drug delivery
ebruary 2006 companies. Moreover, because large pharma require F From the mid-1990s, consolidation in the industry multiple, blockbuster drugs to reach double-digit made partnering with big pharma more difficult and growth on an annual basis, smaller or niche markets more risky for the drug delivery company. As the are left untouched. This opens up product opportunities industry consolidated both in the branded and generic in the market where there is relatively little sectors, drug delivery companies had fewer potential competition. In most cases, large pharma will not
Drug Delivery Technology Drug Delivery Technology partners with large life-cycle management and consider developing a product that does not have peak
24 dynamics and hasin-licensedrightsto late-stage hastaken advantagePharmaceuticals ofthemarket products.Endo specialty pharmaceutical technologyproprietary todevelop strong somevery able tousecreative product conceptdesignand deliveryopening inthemarket, drug companies were under$500million. room formarket entry With this sales potentialofover $500million. There isa lotof FIGURE 2 FIGURE 3 partnering or acquiring the needed drug delivery oracquiring theneededdrug partnering coming off patent, large genericcompaniesare already approved product(Figure 5). y delivery productsapproved throughoutthepast10 e advanced delivery drug technology, butthisisthe e e Novel MolecularEntities(NMEs). There islittle companies andwould bemoreoftenemployed with w w look athow delivery drug productshave evolved as indicator ofchangeintheindustry. Itisinterestingto development onsomelevel (Table 3). stated thatthebusinessplansnow include product publicly delivery tradeddrug companieshave openly and 2areintransition(Table 2). The majority of companies, 3arespecialtyPharma, or pharmaceutical have beenacquiredby delivery otherdrug companies the trendtoward Ofthe10companies,5 integration. strong in1995withtheirstanding2005,highlights developmentinternal projectsunderway (Figure 3). 400 companies,andmany ofthetopcompanieshad among others.By2005,thenumberhadgrown toover included ALZA, Elan,Jago,andNovenAlkermes, sponsorship frombigpharma. The key players in1995 companies anddidnotdevelop productswithout companies claimedtobepureplay delivery drug deliverydrug companies. The vast majorityofthese have madethetransitiontoproductdevelopment. deliveryspecialty productsfromdrug companiesthat vidence thatthishascometopass. There aresome xception rather than the rule. xception ratherthantherule. The majorityofdrug launchedwith xamples ofNMEsthatwere first ears areexamples oflife cycle managementofan ould move earlierintothepipelineofbigpharma ell (Figure 4). Itwas delivery thoughtthatdrug As many delivery ofthe leadingdrug productsare Business modelsarenottheonly important Comparing 10 drug deliveryComparing 10drug companiesthatwere In 1995,therewere approximately 200established DRUG DELIVERY PRODUCTS 25 Drug Delivery Technology February 2006 Vol 6 No 2 26 Drug Delivery Technology February 2006 Vol 6 No 2 gain theneeded technology. This was notthecase, withoracquireothercompaniesto willing topartner delivery drug capabilities,andare strong internal companies suchasSandoz, TEVA, andMylan,have as genericproducts(Table 4). The leadinggeneric ke technology tolaunchequivalent products.Many ofthe y drug deliveryy drug productsof1995 arenow available T T ABLE 4 ABLE 2 gr delivery feltsome in thelate1990s,drug industry companies.Beginning sales andinnumbersofstart-up in agrowth cycle formorethan30years inproduct in thisindustry. delivery wasThe drug industry mainly companiesandproducts,especially regarding specific clear thatadecadecanmake bigdifference avery an extraordinarily timeinthebigpictureitis short branded productsthatoffer market differentiation. technology tothedevelopment isimportant ofstrong, a brandedplay delivery andunderstandthatdrug many genericcompaniesareinterestedin Furthermore, tosuccessfullypartnerships launchgenericversions. deliverydrug technology eitherthroughacquisitionor come off patent,genericcompanieshave theinternal Currently, delivery asmajorbrandeddrug products interested inpaying upfrontpayments androyalties. generic industry, andgenericcompanieswere not w deliverythroughout the1990s.Mostdrug companies The traditional drug deliveryThe traditional drug modelwas beginning to companies(Figure 6). reliance onbigpharmaceutical ere notable orwillingtolicensetechnology tothe o wing painsfromincreased competitionandthe While adecadeinthelifecycle ofany is industry T ABLE 3
28 Drug Delivery Technology February 2006 Vol 6 No 2 throughout the next 5to10years, including that areexpected tobeextremely successful deliveryThere aredrug productsunder development as anumberofkey productsareexpected tolaunch. market willcontinuetogrow intothenext decade forrevenuereliance onbigpharma andgrowth. leaders began toquestionthewisdomofcomplete show signsoffailure. Wall Streetandindustry Now, delivery itisexpected thatthedrug FIGURE 4 FIGURE 6 Exubera ev deliveryDrug business modelswillcontinueto continue toacquireanddevelop key technology. biotech,andgenericcompanieswill pharma, Exubera from Sanofi-Aventis for $1.3billion. at press hadacquired time, Pfizer therightsto w remain aneed fordrug ell-defined, deepexpertise. ell-defined, olve asthemarketmatures; ® (Pfizer/Nektar) and others. (Pfizer/Nektar) FIGURE 5 delivery ♦ however, therewill
companies with Editor’s note: Big
30 Drug Delivery Technology February 2006 Vol 6 No 2 the lungsby anMDIis,ofcourse,the and HFA-227ea. appeared tobesuitable, HFA-134a and intheend, only two propellants w and efficacy. ReplacingCFCs in theirsafety ofconfidence high degree anditsendusers(thepatients) a industry MDIs hasgiven thepharmaceutical as always task, goingtobeadifficult propellant plant wascommissioned atINEOS’ 1995, the world’sfirststand-alone medical d is steadilyincreasing. introduced, and the proportion of HFA toCFCMDIs hy of r chlorofluorocarbons (CFCs),butinresponse tothe ma used for drug delivery totreat pulmonary disease for equirement tophasethese outunder the provisions eveloped during the early1990s, and inOctober The bulkofmaterial delivered to Almost 50years ofCFC-powered
dr the Montreal Protocol, formulations using ny HFA 134A:THECFC M MDIs containing HFA propellants begantobe o
fluoroalkane (HFA) propellants havebeen etered dose aerosol inhalers(MDIs) havebeen years. Historically, the propellants usedwere REPLACEMENT By: A DecadeofLeadership Manufacturing: Medical Propellant Tim Noakes, PhD,and Mark O’Sullivan then, almostunheard of,presenting drug. This approach was, until controlled tothesamestandards asanew rigorously tested, manufactured, and require thesenew excipients tobe naturally cautiousabouttheiruse. authoritiestobe caused theregulatory been usedinmedicalapplications, neither ofthesepropellantshadever y with thepotentialdaily use over many of theemittedformulation. This, coupled propellant, which canamountto99.9% ears by that apatient,andthe fact It soonbecameclearthatthey would INTRODUCTION issues thathavehadtoberesolved. that plant wascommissioned, and some of the the medical propellant manufacturing industry since d approaching its18thbirthday. Thisarticle, will n th of the same equipment thatmade technical grades me break withthe past, aspreviously propellants for grade HFA 134a.Thisrepresented afundamental (then ICI) Runcorn, UK,facility tomake medical- etail the continuing improvements and changes in ow 10yearsold, and the Montreal Protocol is dical useshadbeenproduced and finished on That firstpharmaceutical grade 134aplant is e gas. unsuitable ofthenew formanufacture reject thistraditional approachasbeing to picking” regime. INEOSwas thefirst applied underwhat amountedtoa“batch with varying ofextra degrees controls plants, supplied fromrefrigeration-grade meet theserequirements. considerable challengesinorderto with the propellantmanufacturers Existing CFCpropellantswere A NEWTYPEOFPLANT purity medicalgrade. under rigorousconditions toproduceahigh- 134aandpurifyingitfurther refrigerant-grade propellant “polishing”facility, taking 1995, was theworld’s suchmedical first openinginlate atRuncorn, Fluor constructed w Practice(cGMP)guidelines Manufacturing Good with therequirementsofcurrent f HFA-134adedicated pharmaceutical-grade of the1990s.Itwas clear that only aseparate, HFAs inthedeveloping regulatory INEOS’ ZEPHEXPlant acility thatwas fully validated andcomplied ould beappropriate. The plant thatINEOS climate FIGURE 1 other suppliers, as it is important thata other suppliers, as itisimportant it’s 134aonly containedafew), but ofall have beenamuch easier taskforINEOSas only (which ofthatmanufacturer would full sweep ofpotential134a impurities,not These methodsmustbeable todetectthe v developedmethods, oftenspecifically and analyticalproduction asset.State-of-the-art is composedofmuchmorethanjustthe alidated fortheapplication,are critical. A modern medicalpropellantsofferingA modern NOT ONLY APLANT W in andwhat markets they aresupplying. theydepending onwhat arebased country tend tovary, facilities manufacturing ingredient (BPC) manufacturers arenot (BPC)manufacturers ingredient these propellantsatelevated temperatures. INEOS now possesses5-year GMPdatafor submissions. not beincludedinregulatory w Celsius,butasthedata hundreds ofdegrees they arestable uptotemperatures of propellants provides ampleevidence that ofthese refrigeration useoftechnicalgrades asparallel“technical”datainthe bizarre, propellants. Inonesense,thiswas alittle outextensivecarry stabilitytrialsonthese required, have andallmanufacturers hadto the stabilityofHFA-134a was clearly any requirementsforsuchdata. regulatory for suchalongtimethattheirusepredated theypropellant, andinfact, have beenused stabilitystudiesofthe without formal convincingly demonstrated“inthefield” many years, hadtheirstability stability data.CFCshaving beeninusefor g tests –non-volatile residue(atestforoil& taken over themoremundanebutcritical chromatography method, caremustalsobe addition tothemultimilliondollargas to levels typically of1ppmorless.In detecting allpossible 134aimpuritiesdown of asuitenew methods,capable of authorities. other impuritiestotheregulatory supplier canalways prove theabsenceof rease), odor, andmoisture. as usually notfromaGMP study, itcould ithin theEU, BulkPharmaceutical Regulatory inspections ofpropellant Regulatory However, asanew propellant,dataon A further, new requirementwas for At INEOS,thisledtothedevelopment INSPECTION 31 Drug Delivery Technology February 2006 Vol 6 No 2 32 Drug Delivery Technology February 2006 Vol 6 No 2 September 2001. the schemestarted, andZEPHEX227in ZEPHEX 134ain August 2000,shortly after applied to APIs. INEOSgainedapproval for assessed againsttheICHGMP guidelines inspection program where itsGMPis MHRA, isable tovolunteer foraregular by embracedthisview and INEOS hasfirmly (APIs). Active Ingredients Pharmaceutical the lungevery day, insomecasesforlife,as critical propellants,which areinhaledinto authoritiestendtoviewregulatory these automatically inspected.However, An InsideLookattheCompany’s Lab
being underthejurisdictionofUK FIGURE 2 progressing requirements ofcGMP. As a required tokeep upwiththeever- program ofcontinuousimprovement is But toremaincompliant,avigorous f on astimehasgoneby. back andseehow muchthingshave moved standards, butitisamazingnow tolook w however.start, Backin1995,INEOS plantisonly the propellants purification acility compliantwithGMPat that time. orked towhat were thenthelatest In 1995,thefocuswas todeliver a Successful commissioningofamedical STANDARDS CHANGING leading toeven higherlevels ofcGMP. including provides numerousotherbenefits, ofthechoredatacheckingand from part into thelaboratory, which freesanalysts ManagementSystem(LIMS) Information introduction ofafully validated Laboratory INEOS’, thismakes thecasefor samples fortheQCLaboratory. processing generatesahighvolume of relianceonanalysis of This integral aspart rather thanby monitoringplantvariables. byof performance in-processanalysis, g being removed, today’s pharmaceutical- v considered mature enoughtoinstalland relatively recently thatthetechnology was e generated. LIMSsystemshave beenin basedontheresults produce reports etc,andto compliance withspecifications andresultsgenerated,tests performed all samplesreceived intothelaboratory, all handling errors. A LIMSallows trackingof of raw data,andreductioninmanualdata w improvements tosample significant data handling. documentation, throughpackagecontrolto procedures inmany areas;from otherwise. This hasledtoimprovements in be draggedalongby events, or regulatory standards forward, ratherthaninany sense strategy istocontinually drive new INEOSFluor’sleader initsfield, active xistence sincethe1970s,butit is notuntil alidate suchasystem. rade HFA plantdesignrequiresmonitoring orkflow, throughputandcontrol laboratory In the case of a busy facility,In thecaseofabusy suchas Due tothetraceamountsofimpurity The useofLIMShasresultedin THE BENEFIT A BUSY LAB OF LIMS The current generation of LIMS the propellants) are very nervous about BIOGRAPHIES includes client/server systems integrated multiple sourcing, and are often restricted into the desktop PC Windows environment. by regulatory arrangements as well. In Dr. Tim Some of the current systems have been consequence, a good On Time in Full Noakes trained as an designed from the ground up with cGMP (OTIF) performance by a propellant supplier organic fluorine and CFR21 Part 11 compliance in mind. In ceases to be a luxury and becomes a chemist at 2002, INEOS Fluor chose LabWare as its necessity. Certainly, at INEOS, this is one Manchester LIMS provider. A joint project to install and on a number of quality metrics that are University, UK, in the 1970s. He validate LabWare LIMS was extremely watched very closely. joined ICI in successful and resulted in a robust 1975 and has installation of this industry-standard THE FUTURE since worked on a wide range of software package. technical projects, spanning chemistry, If the past 10 years have taught the laser technology, electrostatics, and crop protection; with an emphasis on propellant supply industry anything, it’s that PRODUCT QUALITY atomization science and technology. In standards do not stand still, and HFA MDI 1989, he joined the HFAs business of It takes time and experience that can propellants are a long way from being ICI and became deeply involved in the only be gained by extensive production for a mature. Looking in INEOS’ crystal ball, all technical aspects of the CFC/HFA transition from a medical propellant manufacturer to really fine-tune a sorts of interesting possibilities can be seen, supply standpoint and has since become purification process, so over time, there has some which can only be shared with a recognized international expert on the been a tendency for specifications to tighten customers, and some of more general subject. In early 2001, ICI sold its as companies learn the optimum operating interest. fluorocarbon business to the INEOS conditions for their plants. With INEOS, It can be expected that the drive to group, where it became INEOS Fluor, and today, he is the techno/commercial tighten specifications will continue, although this has resulted in some of the tightest leader of the INEOS Fluor medical propellant specifications in the world. the emphasis will move away from “9s propellants business. He is based at Chasing” on the related impurity clauses, Runcorn in the UK, near Liverpool. EXPANDING THE SCOPE though lowering limits of detection may still make this a challenging area of Quality Mr. Mark In the days of CFC supply, a “medical” Control. The focus is already switching to O’Sullivan propellant manufacturer believed it had apparently basic, but critical, requirements is a graduate fulfilled the contract when the product was like odor and particulate content control. of the Royal Society of delivered to the user. Nowadays, this is just Suppliers will be expected to ensure that Chemistry and one part of a wide-reaching package of propellant, even though some of the assets is the leader of assistance and support it is expected and that handle it belong to the MDI the INEOS Fluor propellant willing to give. This covers many aspects manufacturer, arrives at the filling turret in 2 ol 6 No V but includes engineering support in the condition it was when made. analytical laboratories in the UK. He was key in propellant handling, acceptance testing via It must always be remembered that establishing the QC laboratory when an independent contractor, which relieves these propellant gases are taken, in relatively the new medical 134a plant was ebruary 2006 the end user of much of that chore, and a large amount, into the often-compromised constructed at Runcorn, and since F highly responsive logistics and transport respiratory tract of a patient for life. As then, has been a leading contributor to the refinement of the quality of system. such, it is INEOS’ view that only the best is the INEOS Fluor medical propellants This last characteristic may seem a acceptable for both the manufacturing and offering. He has expertise covering little mundane, but is in fact crucial to handling of these products, and that a good a wide swathe of analytical techniques efficient use of the new HFAs. Most users comparison, for care, control, and rigor from state-of-the-art gas chromatography through to moisture (because of the technical sophistication of would be water for injections. Drug Delivery Technology determinations. 33 34 Drug Delivery Technology February 2006 Vol 6 No 2 hundred, afew were poisonedtodeath, and achieved onperhaps onepatientoutofa than thehost. A miraculouscurecouldbe hopefully killedtheinfectiousagentfaster treated withapoison-like arsenicthat syphilis ormalaria,inwhich thepatientwas ancient treatmentsforinfectiousagentslike surgery. These approachesare akinto radiation isflawed forreasonssimilarto h patients now [using radical mastectomy].” Iasked if cancer treatments when Icancure 97%of my to me, “Idon’t understand the need for new breast was approached byayoung breast surgeon who said re ago aftergiving apresentation onnew methods to ex grateful patient whose lifehasbeensaved. An collateral damage isexpected tobeacceptedbya loss of organ function. ex re chance of success incancer treatment, issurgical primitive option, and the one thathasthe most “high-tech primitive.” The leading high- tech performed many yearsago. Let’scallthisapproach premise and results remain much the same as sophistication and complexity, butthe underlying primitive. The technologies havegained in er patients were pleasedwiththe lossof one or du m ample of thiswasdriven home tome several years cision may behorrific and include mutilation or T CURRENT APPROACHES reating cancerwithchemotherapy or oval of the lesion. Sadly, the side effectsof M The focus of surgery istosavelife, whileany ce the side effectsof breast cancer treatment. I ethods usedtotreat cancer are stillrelatively & CHALLENGES techniques, such ascouplingtoxic agents have includedanumber ofunwieldy the toxic effects tocancercells confine w tothecanceroustissue must beconfined chemotherapy, theeffects ofthetreatment remains largely unchanged. used today, butthefundamentalparadigm chemotherapy orradiationregimens tobe care standardsallow potent very treatment andweren’t helped. Advances in sickfromthe the majoritygotvery hile sparing normal tissue. hile sparingnormal Attempts to To
significantly improvesignificantly INTRODUCTION confine their effectstodiseasedtissue. treatments thatreduce effectsonnormal tissueand by the FDA are adding momentum tonovel cancer tissue-sparring endpoints for licensure of treatments approaches like lumpectomy for breast cancer. New procedures and implementing tissue-sparring ma g patient’s lifeisthe onlything thatcounts isfinally when Iasked abouttheir patients’ quality of life. prostate cancer, and got the same shocked responses similar comments voiced byphysicians who treat the exactly oppositeopinion. Similarly, Ihaveheard pictures and askagroup of women and youwillget are cosmetically acceptable. Take the same setof lumpectomy and seeresults thatthe surgeon says r the patient’s lifeafterher work.She grudgingly though thiswasanew thought aboutthe quality of both breasts. She reacted inshock and surprise, as esponded, “Iguessthey aren’t.” oing outof fashion. Renewed efforts are being de Fortunately, the attitude thatsaving the Anyone canlookatavariety of Internet siteson
to improve quality of lifebyrefining surgical immunologic response istriggeredby an almost any large, exotic molecule. An lookslike,of what itgoesafter “normal” wo threatening. Becausetheimmune system can producesideeffects thatcanbelife subset oftumors.Further, theseproducts are thereforeeffective only on alimited tumormarkers, and forcertain specificity offer tomanufacture, limited difficult based onthesetechnologies have been v with monoclonalantibodiesandusing arious encapsulationtechniques.Products rks by maintainingadetailed“picture” By: By: Craig Dees, PhD Craig Dees, PhD
36 Drug Delivery Technology February 2006 Vol 6 No 2 only one epitope inany antigen. Therefore, therapies. Antibodies are directedagainst against antibody-derived antitumor also workssensitivity andspecificity limiteffectiveness.further immune systemsresponse,which may reaction may “brake” inthe beanimportant idiotype reaction). The anti-idiotype tothehost(idiotype:anti- configuration the antibodyhastopresenta“foreign” possibility. Additionally, thebindingsiteof threatening consequencesisalsoa but asevere anaphylactic responsewithlife- will negate theeffectiveness oftreatment, immediately. least This responseatthevery trigger animmunologic responsealmost monoclonal antibodyofhumanorigincan response. Couplinganantitumoragenttoa large molecule virtually guaranteesa ”soalteration ofanormal “altered-self cells whereas cancerous tissue(right)shows extensive uptake intocancercells. Drug present innormaltissue(left)islocatedprimarilyfluidssurrounding Distribution of PV-10 ismonitored inmousetissueusingmultiphotonmicroscopy. h muesses exquisite The immunesystems’ FIGURE 1 ev a fractionmay actually respondtotreatment antibody treatment. Ofthosepatients,only be candidatesforanti-estrogen-receptor little as20%ofbreastcancerpatients may government cancerfacility. Inreality, as cancer researcherinaprominent cancer” astoutedinthepopular pressby a from“acure for cry approach isafar antibodies totreatbreastcancer. This anti-estrogen-receptor monoclonal these tumors. Another example isuseof receptor levels generally aren’t elevated in no useinprostatecancerbecausefolate- anti-folate-receptor antibodieshave littleor to alimitedsubsetoftumors.For example, occurs when theantigentarget isconfined w monoclonal-targeted therapy thatworks one patientmay precludeeffectiveness by a epitopein a slightalterationinspecific ell inothers. A morecommonproblem en thoughthey have estrogen-receptor- the treatment. A number ofattemptstouse w therapy can alsobeused.Combiningboth delivery of agent. Lesion-specific specific of chemotherapy, onecandesignatumor- e limited ineffectiveness andtremendously chemotherapy agentsislikely toremain Therefore, large moleculetargeting of antibody asforeignandneutralizesit. recognizes theanti-estrogen-receptor may alsobethatthehost’s immunesystem antibody sothatitcan’t binditstarget. It the estrogen receptorepitope targeted by the some patientsthereisasubtlealterationin cells modulateoff the receptororthatin is alsopossible thatthereceptor- positive penetrate tissuetogettheneededsites.It large antibodies (160,000Daltons)don’t positive tumors.Itmay bethatthevery xpensive. c fromthe Aslightnodagreement time.” this weare onlybuyinghimalittlemore therefore withall of killingallthetumor, “We don’thave achance decision. Hesaid, assistant’s commentontheeffectsofthis closer tothebigvein.More tellingwas the decided tostopinsertingtheprobeany r w v surgeon was “you betterhopethere isa Theresponse fromthechief vena cava.” the happen ifwegettoocloseandburn “Whatwill the venacava. Heasked, comment ontheclosenessoftumorto Iheard oneofthesurgeons tumor, As theprobewas beinginsertedintothe oftheRFdevice.monitoring performance andacompanyrepresentative the tumor), images andactuallyplacetheprobeinto r a multiplenurses, two surgeons, cava veins.Iwatched asurgical teamof closelytotheportalandvena situated very alarge tumorwas liver function. Also, riskingadverselycompromised liver tissue, tumors would require removal oftoomuch liver onmultiplegrounds. The numberof considered acandidateforresection ofthe lobe ofhisliver. The patientwasn’t on apatientwithmultipletumorsinone radiofrequencyroom toobserve ablation c fromthe Aslightnodagreement time.” this weare onlybuyinghimalittlemore therefore withall of killingallthetumor, “We don’thave achance decision. Hesaid, assistant’s commentontheeffectsofthis closer tothebigvein.More tellingwas the decided tostopinsertingtheprobeany r w v surgeon was “you betterhopethere isa Theresponse fromthechief vena cava.” the happen ifwegettoocloseandburn “Whatwill the venacava. Heasked, comment ontheclosenessoftumorto Iheard oneofthesurgeons tumor, As theprobewas beinginsertedintothe oftheRFdevice.monitoring performance andacompanyrepresentative the tumor), images andactuallyplacetheprobeinto r a multiplenurses, two surgeons, cava veins.Iwatched asurgical teamof closelytotheportalandvena situated very alarge tumorwas liver function. Also, riskingadverselycompromised liver tissue, tumors would require removal oftoomuch liver onmultiplegrounds. The numberof considered acandidateforresection ofthe lobe ofhisliver. The patientwasn’t on apatientwithmultipletumorsinone radiofrequencyroom toobserve ablation I I ould further potentatethe effectivenessould further of adiologist andassistantatthatpoint adiologist (toread theultrasound andMRI adiologist andassistantatthatpoint adiologist (toread theultrasound andMRI ascular surgeon onthisfloorbecausewe hief surgeon was hisonlyresponse. ascular surgeon onthisfloorbecausewe hief surgeon was hisonlyresponse. ntb bet ls h on. The on’t beabletoclosethewound.” ntb bet ls h on. The on’t beabletoclosethewound.” w w To as recently invitedintoan as recently invitedintoan
improve theeffectiveness andsafety operating operating critical vasculature. treating thetumor forfearofdamaging cryoablation may beequally ineffective in near majorblood vessels, RFand tumor isnon-resectable duetoitslocation focused techniques.For example, ifaliver effectiveness andsafetysimilar tootherless- the rightdirection,remainhampered intheir such asRFandcryoablation, while astepin threatening sideeffects. Ablative techniques, effectiveness andriskssevere orlife- tissue. ablating normal This limits tissue becausethey areequally effective in theireffects soley todiseased to confine common. However, thesetechniquesstillfail into liver tumorsunderultrasoundguidanceis US, percutaneousinjectionofabsoluteethanol tumors totheliver isavailable. Outsidethe ormetastatic (RF) orcryoablation ofprimary prominent example. IntheUS,radiofrequency therapy ofliverspecific tumorsisone these methodshave beendeveloped. Lesion- Human T * Similarresultshavebeenobtainedwithothertumorlines, includingrenalcarcinoma,multiple- T C- E+ 4/4 MCF-7 (ER+) C- E- 4/4 T MCF-7 (ER-) T-3 4/4 HTB-133 T able 1.Treatment of HumanBreast Tumors sarcoma, caninebladdertumor, andfelinesquamousepithelialcarcinoma. tumors treatedinanimalpatientsinclude:cutaneousmelanoma,equinesarcoid,caninefibrous drug-resistant lungcarcinoma,hepatocellularandprostatecarcinoma.Spontaneous 4D4/4 -47D able 1.Treatment of HumanBreast Tumors umor CellLine* (Lab AnimalModel) (Lab AnimalModel) w delivery acid.Inone study, ofbattery 5-FU agent have littlemoreeffectiveness thandirect gained acceptance. The effects ofthistype with solittlesuccessthatthisapproach hasn’t av severe systemicsideeffects canoccur. fordiseasedtissue, the agentisn’t specific outside theareabeingperfused, andbecause the highly toxic agentwill gainaccesstotissue and deliver ahighdoseofagent.Eventually, supply tothetreatmentsite foralimitedtime Basically, onetriestoclamportieoff blood melanoma andfornon-resectable liver tumors. perfusion forthetreatmentofmetastatic Examples ofthesetechniquesincludeisolated of ahighly toxic andconcentratedagent. theareatreatedby limitingdiffusion confining agents while increasingeffectiveness is attempted tolimittoxicity ofchemotherapy as delivered intratumorally intocutaneous ailable antitumoragentslike 5-FUhave met Direct intralesionaldelivery ofcurrently Another techniquethathasbeen Mice Cur ed reasons, market issues. forces,andregulatory through anumber ofmedicalandtechnical these applications was by determined sorting breast carcinoma,andliver tumors.Choiceof intralesional treatmentofcutaneous melanoma, for avariety ofapplications,including to advance apre-existing compound(PV-10) get aproducttomarket rapidly, ithaschosen “new thatonly drugs” target diseasedtissue,to tissue. Even thoughthecompany hasasuiteof target onlyones willspecifically diseased which anddetermine human safetyprofiles screen pre-existing compounds withknown diseased tissueisknown, Provectus canrapidly because themechanismoftargeting toonly initially viaintralesionaldelivery. Further, the chanceofsuccessby usingthe agents delivery we have, ithaschosentomaximize have shown thattheagentscanbeeffective by though thecompany’s initialpreclinicalstudies todiseasedtissue.Even completely confined compounds whose effects arealmost Inc.hasdevelopedPharmaceuticals, asuiteof additional margin ofsafety. Provectus andprovidepotentate theefficacy an agentcanfurther delivery oftumor-specific that only affects diseasedtissue.Intralesional safety, tumorsmustbetreatedwithanagent lead tosevere systemicsideeffects. entire bodytotheeffects thatcan ofthedrug agentsstilleventuallynon-specific exposes the use ofintralesionaldelivery ofhighly toxic and treated. As inthecaseofisolatedperfusion, effectiveness toabout4outof14tumors addition ofepinephrineincreasedthe couple ofdozentreatedresponded. The melanomas. Only acoupleoftumorsout To
gain maximumeffectiveness and TUMOR-SPECIFIC SOLUTION 37 Drug Delivery Technology February 2006 Vol 6 No 2 38 Drug Delivery Technology February 2006 Vol 6 No 2 confined tothetumor. confined Any thatdoesn’t drug intralesionally, itanditsantitumoreffects are in tumortissue. When PV-10 isgiven systemically, willremainselectively localized 7.2 to7.4). Therefore, PV-10, when given tissue(eg, pH6.4to6-7compared to normal usually isacidiccompared tosurrounding ideal forthis. The intratumoralenvironment the intracellularconditionsintumortissueare saline intoahydrophobic environment. And as thediluent,PV-10 outofthe willpartition asasolutionwithinjectableformulated saline (approximately 10%w/v).However, when tissue. PV-10 hasasahighsolubilityinwater antitumor effects almostexclusively tocancer its solvent and conditionswillconfine are routinely cured (5/5). treated miceresolve, andthetreated area isdifficulttodiscernlater. Allmice the effectsof PV-10 are confinedtotumortissue. Smallwounds seeninPV-10- damage isdonetosurrounding normaltissuethantodiseasedtissue. Incontrast, delivery isineffective inresolving thetumors andcures nomice(0/5).More Chemoablation of aliver tumorinamousemodelusingethanolviaintralesional PV-10 (RoseBengal)when intheright MECHANISM OFTUMOR SPECIFICITY FIGURE 2 receptors toenter thecell.PV-10 would then receptor-mediated processeslike lipoprotein receptors). PV-10 may alsotake advantage of many receptorsiselevated (eg, lipoprotein many cancercells,thereceptordensityof PV-10 intothemembrane. Additionally, in w alterations, themembranefluidityishigher, fully known. However, amongother allow PV-10 toselectively enterthemarenot conditions thatexist inthediseasedcellsthat at thecellularlevel (Figure 1). The itseffects tothesecells cells, thusconfining membranes ofcancerandotherdiseased an intramusculardepot). injected intravenously, and7-hourhalf-lifeas tissue(30-minutehalf-lifewhenfrom normal tissue.PV-10normal israpidly eliminated associate withtumorcellsisclearedfromthe hich isadvantageous of forpartitioning Further, PV-10 only intothe partitions contents inaprocess thatmimicsthenormal l oflysosomalintegrity membranes. The with diseasedcells,PV-10 the disrupts environment idealforPV-10. Onceassociated ve Further, theintralysosomal environment is ofPV-10partitioning intothemembrane. fluid) inthelysosomal membrane isidealfor pathway. The compositionofthelipids(highly l process thatresultsincelldeath.Releaseof ofthecellular part enzymes areanimportant “suicide.” Lysosomes thatcontaindegrative through which cellsnormally commit effects by stimulatinganaturalprocess it isassociated. complex hydrophobic moleculeswithwhich tothelysosomesbe transported alongwith ysosomes rupture orleak,releasingtheir ysosomes rupture ysosomal contentsisanearly step inthe A w Inever andifitcomesback, feel safe, “Ihave 2more years togo continued, He I was sosick Iwanted todie.” they triedtokeep thedruginmyliver, “Eventhough 3 years before. Hesaid, treated by organ perfusiontherapy about andhadbeen liver cancersurvivor fund managerrevealed thathewas a the neartheendofmeeting, Finally, throughout aseveral-hour discussion. treatment oflivertumors. This wenton k oneparticularfundmanager of tumors, spectrum applicabilitytoawidevariety broad new antitumoragenthasvery Even thoughProvectus Pharmaceuticals’ company isdevelopingaproductfor. or someoneclosehasadiseasethatthe a particularcompanysolelybecausethey number ofinvestorsthatare attracted to Iamcontinuallyamazedby the investors, company thatmustinteract dailywith A w Inever andifitcomesback, feel safe, “Ihave 2more years togo continued, He I was sosick Iwanted todie.” they triedtokeep thedruginmyliver, “Eventhough 3 years before. Hesaid, treated by organ perfusiontherapy about andhadbeen liver cancersurvivor fund managerrevealed thathewas a the neartheendofmeeting, Finally, throughout aseveral-hour discussion. treatment oflivertumors. This wenton k oneparticularfundmanager of tumors, spectrum applicabilitytoawidevariety broad new antitumoragenthasvery Even thoughProvectus Pharmaceuticals’ company isdevelopingaproductfor. or someoneclosehasadiseasethatthe a particularcompanysolelybecausethey number ofinvestorsthatare attracted to Iamcontinuallyamazedby the investors, company thatmustinteract dailywith ry ept askingmequestionsonlyabout ept askingmequestionsonlyabout ant tobetreated thesameway again.” ant tobetreated thesameway again.” s adirector ofasmall s adirector ofasmall
At thesubcellularlevel, PV-10 exerts its acid (pH4.0),which makes the pharmaceutical pharmaceutical BIOGRAPHY
Dr. Craig Dees is the Chief cascade of events that occurs when cells Currently PV-10 is being tested Executive Officer of Provectus undergo apoptosis. Therefore, cell death is in a Phase I clinical trial of Stage III Pharmaceuticals, Inc. He has spent not like that produced by a toxic agent but melanoma patients treated by intralesional more than 20 years in Senior more like the normal cell “suicide” process. delivery. The Phase I trial is primarily a Management positions at Photogen Further, PV-10 doesn’t enter the nucleus or dose-escalation study for safety. However, Technologies, Inc.; the Oak Ridge work by damaging genetic material. PV-10 because the systemic safety profile is National Laboratory; LipoGen, Inc.; isn’t carcinogenic, mutagenic, or likely to be known for this agent, the initial doses and TechAmerica, Inc. Dr. Dees was teratogenic, especially when delivered by an are at anticipated efficacy levels, allowing a Founder, Senior Scientist and intralesional route. Therefore, the possibility us to assess both safety and initial Founding Director of Photogen is remote for long-term sequalae of a second effectiveness in Phase I. A similar Phase I before Provectus was formed. His tumor in contrast to that of most current clinical trial on breast cancer patients is responsibilities have included anticancer therapies. being performed at efficacy levels. product design and development To date, early results from these trials in the fields of ethical vaccines, are similar to the results observed in cosmetics, human diagnostics, and PERFORMANCE tumors in experimental animals and with over-the-counter pharmaceuticals. IN VIVO spontaneous tumors in animals. No severe His development record includes local or systemic adverse events have been the first live viral vaccine produced As shown in Table 1, a small volume reported, and complete ablation of tumors by recombinant DNA technologies of PV-10 delivered intralesionally results in has been observed. and the first recombinant antigen resolution of all breast tumors in a In conclusion, where previous human diagnostic assay. Dr. Dees laboratory animal model. Figure 1 shows attempts at using highly toxic has also successfully licensed a that there is no apparent damage to chemotherapy agents have had little number of proprietary cosmetic surrounding tissue. This has been success and the effects were not too products. In addition to design confirmed by histopathologic examination dissimilar from using a highly concentrated and development activities, he has of the effects on these tumors. As shown in acid, the key to success using intralesional been responsible for business and Figure 2, the tumors rapidly resolve, and delivery is to combine the method with an market applications, regulatory the treated animals have been held up to a agent like PV-10 whose effects are affairs, and commercialization of year with no return of tumors at the confined to diseased cells. Laboratory human and veterinary medical primary or a remote site. For most tumor studies using tumor models and treatment products. Awards include an R&D models, one treatment results in cure of the of spontaneous tumors have validated this 100 for an industrial enzyme, an ol 6 No 2 ol 6 No animals. However, on a rare occasion due approach, while early response in human Inventor’s Forum New Product V to a defect in the technique of drug clinical trials is similar to that of the Award for a skincare product, and a delivery, a tumor may not be fully resolved. preclinical animal studies. Clinical trials First Sarber Award for outstanding Because there are virtually no side effects, are continuing in melanoma and breast
research in virology. Dr. Dees earned ebruary 2006 F the tumor can be retreated. This is in stark carcinoma, and are expected to begin his PhD in Molecular Virology from contrast to the use of many toxic soon for liver cancer. the University of Wisconsin, chemotherapy agents in which therapy has Madison, his MS in Immunology to be halted due to systemic side effects, from Auburn University, and his often focused on the immune system, and BS in Microbiology from Brigham resulting in severe immunosuppression. Young University. Drug Delivery Technology Drug Delivery Technology
39 ABSORPTION E N H A N C E M E N T
Promoting the Oral Absorption of Drugs in Humans Using Gastro-Intestinal Permeation Enhancement Technology (GIPET) By: Thomas W. Leonard, PhD; Edel O’Toole, Fiona Brennan, PhD; and David J. Brayden, PhD
ABSTRACT
Overcoming the poor oral absorption of high- ingredient. To date, 300 volunteers have been value therapeutics, including peptides, is one of the administered GIPET formulations in 16 Phase I most important and challenging goals in drug studies of 6 separate drugs comprising both single- delivery. Gastro-Intestinal Permeation Enhancement and repeat-dosing regimes. Oral bioavailability of Technology (GIPET, Merrion Pharmaceuticals Inc., alendronate, desmopressin, and low molecular weight Wilmington, NC.) attempts to address this issue by heparin in humans was increased using GIPET safely delivering drugs across the small intestine in formulations compared to unformulated controls. therapeutically relevant concentrations. GIPET is GIPET was well tolerated by human subjects. Using based primarily on promoting drug absorption fluxes of markers of epithelial permeability, effects through the use of medium-chain fatty acids, salts, of GIPET on the human intestine were shown to be and derivatives (GIPET I), formulated in enteric- rapid, short-lived, and reversible in vivo. The coated tablets. GIPET II comprises mixtures of combined data suggests that GIPET formulations mono- and di-glyceride fatty acids in a solid dose have a real potential as a platform technology for format (Box 1). Importantly, these excipients are safe and effective oral drug delivery of poorly generally regarded as safe (GRAS) and do not result absorbable drugs. in a change in chemical composition of the active
INTRODUCTION they offer a more direct path toward epithelium, or by forming mixed micelles regulatory approval for compounds that are or other sorts of physical interactions In 1995, Amidon and colleagues already approved or are in advanced stages between the drug and the enhancer that recommended the biopharmaceutical of development. Physical techniques can be enhance permeability, or both of these. classification system (BCS) for describing directed toward increasing There have been many attempts to
ol 6 No 2 ol 6 No dissolution/solubility in the intestinal promote oral absorption of poorly V gastrointestinal absorption behavior of drugs.1 The BCS groups drugs into one of milieu, or increasing intestinal wall absorbed drugs throughout the past 15 four classes based on solubility and permeability. Delivery of drugs that are years, but the majority have not been permeability characteristics (Table 1). insoluble but are permeable (Class II in the commercially successful. Reasons for
ebruary 2006 Technologies to enhance oral absorption of BCS categorization) can generally be these failures include the inability to F poorly absorbed compounds can be divided improved with solubilizing approaches, deliver therapeutic levels of drug over a into two general categories, those involving whereas soluble but poorly-permeable sustained period of time and safety issues chemical modification to the compound, drugs (Class III), including most peptides, associated with new chemical compounds and those that depend on physical are amenable to approaches that improve used as enhancers. Also associated with interactions. Those techniques dependent on the ability of the compound to cross the these attempts is the high cost of goods physical interactions are generally preferred gut/epithelial interphase.2,3 This may be (due to the poor efficacy of the enhancer
Drug Delivery Technology Drug Delivery Technology by the pharmaceutical industry because achieved by direct action on the gut system), which results in the need for
40 advantagesthe of multi-phase, multi-compartment capsules are clear
Higher Perceived Value Smaller Capsules Consumers view multi-phase, multi-compartment Hard-shell capsules have thinner wall construction, capsules as having a higher perceived value than allowing them to contain more ingredient in a smaller ordinary tablets, capsules and soft gels. capsule versus thicker-shelled soft gel capsules. Hard shells have faster and more complete dissolution Choice of HPMC or than soft gels. Gelatin Capsules With multi-phase, multi-compartment Less Odor and Less Irritation capsules you are not limited to just Reduces unpleasant ingredient taste and gelatin (animal-based product) but odor commonly found with tablets and have the option of natural HPMC traditional capsules. And, liquids (hydroxypropyl methyl- cellulose) provide less irritation than traditional and alternative capsule materials. delivery methods.
Better Visual Appeal Tamper Proof Sealing Multi-phase, multi-compartment Band sealing reduces tampering and capsules have none of the dust and provides a non-permeable barrier to residue associated with powder retard oxidation and increase shelf-life. capsules. Better visual product appearance translates to higher Unique Appearance perceived value. This new delivery system stands apart from look-alike products that crowd Increased Absorption retail shelves. and Bioavailability Liquids naturally offer faster and Faster Development increased absorption and Multi-phase, multi-compartment availability of active ingredients. capsules reduce the development time compared to bi-layer tablets to get a Increased Profit Potential new product into clinical trials faster. Add up all the advantages. Expect higher sales…and high margins! Compounds Deliver Pharmaceutical, Deliver Incompatible bio-pharmaceutical and nutraceuticals Compounds Deliver incompatible in a single dosage form. compounds in a single dosage form with different release Multi-Phase System profiles. Compounds can be delivered with the most advantageous pharmacokinetic Multiple Release Profiles profile such as liquids and solids Incorporate one or more release profiles into a single dosage form such as immediate, enteric, targeted, chronotherapy and pulsatile.
Patent Pending US-2005-0008690-A1
5420 Bay Center Drive • Suite 100 • Tampa, FL 33609-3425 • (813) 837-0796 • www.innercap.com • [email protected] ABSORPTION E N H A N C E M E N T
FIGURE 1 significant amounts of active pharmaceutical ingredient (API). Lack of reliable and Mean urinary excretion of alendronate expressed as % administered dose from a predictive in vivo animal models and the single dose of GIPET solid dose formulations in humans. Reference: Fosamax®, inability to convert technology into practical 35 mg; Alendronate, Test: 17.5 mg with low (Form 2) or high concentrations of and reproducible solid dosage forms have GIPET I (Form 1). N = 16. Coefficients of variation were: Reference Fosamax® - 33.6%, Form 1 - 40.5%, and Form 2 - 106.8%. also been an impediment to reaching commercial success. GIPET is a platform technology demonstrated to enhance bioavailability of a variety of compounds, most of which belong to the BCS Class III. These compounds include most peptide, polysaccharide, and oligonucleotide molecules that traditionally have been administered parenterally at significant cost and inconvenience to patients. This review provides an evaluation of the technology with a particular emphasis on data that have been achieved in Phase I human trials.
GIPET TECHNOLOGY
In 1991, it was shown that paracellular absorption of polar marker molecules across isolated rat colonic mucosae was increased by medium-chain fatty acids at selected concentrations in vitro.4 Anderberg et al Box 1. Composition of GIPET Solid Dose demonstrated that part of the mechanism of Oral Delivery Technologies action of GIPET I in the in vitro human intestinal cell line, CACO-2, was used to promote absorption across intestinal epithelial GIPET I Technology tight junctions at a concentration of 13 to 16 mM, thereby effecting cytoskeletal changes • Medium-chain fatty acids and salts thereof favoring permeation of small polar molecules.5 • Solid dosage forms (enteric-coated tablets) While it is relatively simple to show enhanced permeation using isolated tissue mucosae or perfused rodent intestinal segments ol 6 No 2 ol 6 No V GIPET II Technology using solutions of excipients with the active, it is another set of challenges to advance a • Mono-/di-glyceride fatty acids preclinical concept to a marketable formulation • Solid dosage forms (enteric-coated soft gel/hard capsule shell) that can be used in human patients. The
ebruary 2006 development of GIPET technologies was F facilitated by the need for solid dosage form GIPET III Technology presentations for oral enhancement techniques. The general format of GIPET dosage forms is • Novel branched, cyclic, and straight chain fatty acids enteric-coated tablets or capsules comprising • Solid dosage forms (enteric-coated tablets and/or capsules) the enhancer system and the drug in an appropriate matrix. Importantly, for GIPET I and II systems, the excipients used as Drug Delivery Technology Drug Delivery Technology
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low molecular weight heparin (LMWH); and a FIGURE 2 peptide, desmopressin. Plasma profile of anti-Factor Xa activity from the oral delivery of LMWH-GIPET I in Alendronate sodium (Fosamax®, Merck) humans. ■ 90,000 IU LMWH/ high dose GIPET; ◆ 45,000 IU LMWH/ low dose GIPET; is approved as both once-a-day and once-a- ▲ SC reference, 3,200 IU LMWH. N = 14 to 16 subjects. week tablets for the treatment and prevention of post-menopausal osteoporosis in women and also for men requiring an increase in bone mass density. Oral bisphosphonates are very poorly absorbed; approximately 0.65% of an oral dose of alendronate is absorbed.7 Bisphosphonates are currently not administered as enteric products as this administration route results in even less absorption. All current oral formulations of bisphosphonates are associated with dysphagia and esophageal reflux. The tablets must be taken in the morning with a full glass of water on an empty stomach to ensure some drug is absorbed, and patients are required to remain upright for at least 30 minutes following administration to minimize esophageal erosion from the gastric irritation. This complex dosing regime severely decreases compliance.8 Injectable bisphosphonates, pamidronate (Aredia®, Novartis) and zoledronic acid (Zometa®, Novartis) are used as chemotherapeutic agents for metastatic bone Table 1. The Biopharmaceutical Classification System cancer.9 Efficacy in this indication requires a (Amidon et al, 1995) greater bioavailability than can currently be delivered orally. The intravenous dosage forms Class II Class I also result in some discomfort, albeit on a monthly basis, and requires patients to spend Low solubility High solubility several hours in outpatient clinics at High permeability High permeability considerable expense. An oral formulation of bisphosphonates with significantly higher Class IV Class III bioavailability would certainly benefit this subgroup of patients. Low solubility High solubility A GIPET I-enhanced alendronate tablet Low permeability Low permeability containing 17.5 mg of alendronate was administered orally to 16 healthy subjects. ol 6 No 2 ol 6 No Bioavailability was compared with that V enhancers were specifically selected due to PHASE I TRIALS OF GIPET achieved after administration of 35-mg their GRAS status. Not only do medium-chain Fosamax® tablets. Urinary excretion data fatty acids enjoy GRAS status, they are also GIPET has been tested in a range of indicated that GIPET conferred a 5-fold
common food components; they are present in doses with six poorly-absorbed drugs in a total increase in the oral bioavailability of ebruary 2006 F milk at a level comprising more than 1.2% of of 16 Phase I studies. Table 2 shows the human alendronate formulations over the reference the total fatty acids.6 GIPET I and II systems oral bioavailability data for the six drugs in compound (Figure 1). This achievement is have been tested orally in rats, dogs, and humans. Overall, a 5- to 14-fold improvement noteworthy from two perspectives. First, it is a humans to establish safety profiles and in oral bioavailability was seen compared to very significant improvement in bioavailability efficacy. The absorption promoter and the drug controls. Detailed pharmacokinetics from over the current formulation. Such should be released at the same rate and at human trials are described further for three improvements in bioavailability should allow appropriate concentrations close to the specific examples, all of which are soluble and expansion of indications for bisphosphonate absorbing epithelium to maximize efficiency poorly permeable compounds: a tablets into those areas that are now treated by Drug Delivery Technology of the drug/enhancer/epithelium interaction. bisphosphonate, alendronate; a polysaccharide, injections. Second, these results are achieved 43 ABSORPTION E N H A N C E M E N T
by enteric-coated tablets, which eliminate FIGURE 3 gastric administration and the associated Plasma profile of the oral delivery of desmopressin-GIPET II in humans. gastric and esophageal issues. ■ Desmopressin-GIPET (200 µg, PO capsule); 3 Desmopressin, Minrin®, Low molecular weight heparin (LMWH) (200 µg, PO tablet); ▲ Desmopressin (4 µg, SC reference). N = 18 subjects. is used as a prophylactic anticoagulant treatment to prevent deep vein thrombosis or pulmonary embolism following hip or knee replacement surgery, and must be given by subcutaneous injection due to its low bioavailability.10 As this is an acute therapy, treatment usually ends when a patient leaves the hospital. Oral warfarin, which has a very narrow safety profile, is often used if therapy is to be continued at home. An oral formulation of LMWH would reduce healthcare costs as it could be easily administered on an outpatient basis, eliminating the need for the intensive therapeutic monitoring that is carried out on new warfarin patients due to its toxicity. LMWH-GIPET I was formulated in coated tablets containing 45,000 or 90,000 IU of a LMWH (average molecular weight of about 4,500) with GIPET I. Oral bioavailability was compared to the standard subcutaneous dose of 3,200 IU following administration to 14 to 16 healthy human subjects. Mean data for the Table 2. Phase I Oral Bioavailability Data With GIPET anti-FactorXa assay over time is shown in Figure 2, and the overall data is summarized in Drug (MW) GIPET Reference Oral Fold Increase Table 3. Oral bioavailability of 3.9% to 7.6% Bioavailability Over Control with respect to the subcutaneous route was (%)** *** achieved. With the 90,000-IU tablet, Alendronate Fosamax® therapeutic levels of anti-FactorXa activity (323) I (oral) 8.4 5 were seen in all subjects, and the responses were sustained in most subjects over a time Desmopressin course comparable to the subcutaneous (1,069) II S.C. 2.4 13 delivery. Oral bioavailability of 8% in humans has also been achieved using GIPET II with LMWH* I I S.C. 9.0 - another LMWH (average molecular weight of (approx 4,500) about 6,000) while up to 18% oral ol 6 No 2 ol 6 No V LMWH* II bioavailability was seen with LMWH in dogs (approx 6,000) I S.C. 8.0 - with GIPET III (data not shown). Desmopressin, a synthetic peptide Antisense I I I.V. 4.9 - analogue of arginine vasopressin, is used as an
ebruary 2006 (6,350) antidiuretic agent for treatment of vasopressin- F Antisense II sensitive diabetes insipidus, polyuria, and (7,284) I I.V. 6.9 - polydypsia.11 Oral bioavailability is low, ranging from below the limit of detection of * LMWH: Low Molecular Weight Heparin the assay to 5%. There is considerable ** % Oral Bioavailability refers to the bioavailability of these compounds using GIPET relative to the intrasubject variation. With a direct parenteral dosage form. relationship between the amount absorbed and *** Fold Increase Over Control is the improvement in oral bioavailability resulting from the GIPET Drug Delivery Technology Drug Delivery Technology formulation relative to an unenhanced oral control. the pharmacodynamic response, an improved oral formulation could lead to better efficacy 44 ABSORPTION E N H A N C E M E N T
SAFETY STUDIES OF GIPET IN Table 3. Phase I Oral Bioavailability Data: LMWH-GIPET 1 CLINICAL STUDIES
PK 45,000 IU 90,000 IU 3,200 IU The Phase I studies on the six drugs that (Pharmacokinetic LMWH LMWH SC Ref. have been carried out comprised 800 Parameters) GIPET 1 GIPET 1 exposures to GIPET in 300 volunteers. In some studies, individuals were safely dosed up Oral bioavailability (%) 3.9 +– 3.5 7.6 +– 4.8 N/A to six times with GIPET formulations in order Coefficient of to show that exposures could be safely given N/A variation (%) 89.1 62.9 on a repeated basis. A legitimate concern with the use of intestinal absorption-promoting Number of technologies is that the epithelium may not 60 100 responders with 100 have time to recover before the next dose. (9/15) (16/16) levels > 0.1 IU/mL (%) (14/14) Although the clinical experience thus far has not suggested that this is an issue in vivo, Number of responders 13 81 intestinal permeability studies were carried out with levels > 0.1 IU/mL 71 (2/15) (10/14) (13/16) in human subjects following intrajejunal (IJ) for > 6 hours (%) administration of GIPET I followed by sugar molecules whose oral absorption is typically Total duration > 0.1 + 2.6 +– 3.6 10.6 +– 5.4 7.1 – 1.3 low and largely restricted to the tight junction IU/mL (Hours) route. The aim was to establish intestinal permeability recovery time in the presence of a typical fatty acid component of a GIPET associated with a high level of compliance. GIPET components enjoy favorable regulatory formulation. The polar sugar, mannitol (MW When desmopressin was formulated in a status. Several regulatory bodies have reviewed 182), is absorbed paracellularly across the gut GIPET solid dose format and administered the data on safety and concluded that the fatty and is excreted unchanged in the urine. Oral orally to 18 human subjects, 2.4% acids and their salts used in the GIPET bioavailability of mannitol is approximately 12 bioavailability relative to the subcutaneous formulations are low in toxicity. 25%, and this amount is retrieved in the urine route was measured. Notably, this value was a For example, the fatty acids used in GIPET because it is freely filtered and not reabsorbed 10-fold improvement over the 0.2% value seen are considered GRAS by the US FDA. When by renal tubules. Another polar disaccharide in this study in subjects who were administered reviewed by the FAO/WHO Joint Expert sugar, lactulose (MW 342), is also absorbed with the currently marketed Minirin® tablet Committee on Food Additives, component fatty paracellularly, but only to a level of 1% due to (Ferring Pharmaceuticals) (Table 4, Figure 3). acids in GIPET were not limited to a specific its larger molecular radius. The ratio of the two More importantly, the CV around the AUCs allowable daily intake because it was judged that agents in urine is a well-established, non- dropped from more than 240% to less than the presence of these materials in food would invasive indicator of human intestinal 90%. The AUC CVs for the GIPET dosage are have no impact on human health.13 Finally, the permeability in vivo.15 similar to those for the injectable product. EU Scientific Committee for Food has reviewed When the tight junctions are open or if the safety data for these excipients and the epithelium forms a less-restrictive barrier, ol 6 No 2 ol 6 No determined them to be safe in use.14 the urinary lactulose:mannitol excretion ratio V SAFETY STUDIES Multiple safety studies of GIPET (LMER) should increase because lactulose absorption should be preferentially increased. In OF GIPET IN enhancers have been carried out in rats and an open label partially randomized study using PRECLINICAL MODELS dogs with the objective of evaluating the
up to 24 human subjects, the marker molecules, ebruary 2006 potential for adverse effects on the F mannitol (2 g) and lactulose (5 g) were given The absorption-promoting excipients of gastrointestinal tract. In these studies, doses of orally at time 20, 40, or 60 minutes following the GIPET technology are approved food up to 1 g per day were given for as long as 4 intrajejunal instillation of GIPET I. The additives in both the US and Europe. The weeks without effect on clinical signs or combined data showed that only when the available data demonstrate the low toxicity of clinical laboratory parameters, and failed to sugars were administered 20 minutes after the fatty acids and their salts, which is consistent produce any gross or microscopic pathology in fatty acid, the urinary LMER ratio increased with their long history of use as food additives. the gastrointestinal tract. (Table 5). Thus, in subjects receiving three Drug Delivery Technology Drug Delivery Technology
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separate doses of GIPET I, the effect of the Table 4. Phase I Oral Bioavailability Data: agent on intestinal permeability was temporary Desmopressin-GIPET II and increases in permeability were reversed at 40 and 60 minutes. Importantly, the three IJ doses of GIPET I were considered safe and well Treatment AUC Last (+–CV%) Relative Bioavailability (+–CV%) tolerated in the human subjects. Furthermore, Desmopressin-GIPET II studies testing the effects of GIPET I on + + 14 (200 µg, PO capsule) 840 – 729 2.4 – 2.9 increasing intestinal [ C]-poly (ethylene) glycol absorption in dogs were similarly suggestive of only a temporary effect of this major component of GIPET (data not shown). The combined data Desmopressin (Minrin®) 159 + 383 0.2 + 0.2 is not surprising because 17 billion enterocytes (200 µg, PO tablet) – – are normally replaced every day, and the entire epithelium of the small intestine is replaced every 5 days in humans.16 Desmopressin 539 +– 517 N/A (4 µg, SC reference) CONCLUSION
GIPET is a mature research-stage AUC Last: Area under the curve; CV%: coefficient of variation; N = 18 in each group technology that has shown significant efficacy in human oral delivery studies of drugs that normally must be injected. The data show that a range of drugs of different structures can be Table 5. Timing of Effect of GIPET I on Human Intestinal delivered to therapeutic levels using two Permeability Using Urinary Excretion of Polar Sugars different solid-dose GIPET formulations. These as a Surrogate Marker include peptides, bisphosphonates, glucosaminglycans, and antisense oligonucleotides. The wide variety of poorly Group LMER (CV) N Statistics absorbed drug types that have now shown efficacy in Phase I trials using the GIPET oral A. Sugars 0.02 +– 0.01 (66.3) 24 - delivery formulations suggests that the delivery system is a true platform technology that can be B. GIPET I 20 mins adapted for a range of biotech cargoes. before sugars 0.03 +– 0.01 (70.4) * 22 P < 0.01 Importantly, Phase I trials using 300 subjects revealed no toxicity of concern and, in addition, C. GIPET I 40 mins this finding was manifested in subjects 0.02 + 0.01 (38.9) 22 NS before sugars – receiving multiple doses of GIPET. Additional human studies revealed that the absorption- promoting effects of GIPET were transient and ol 6 No 2 ol 6 No V D. GIPET I 60 mins 0.02 +– 0.01 (31.9) 23 NS complete in less than 1 hour. The combined data before sugars provides additional arguments that suggest that the absorption promoter and the active E. Sugars 0.02 +– 0.00 (29.5) 22 NS ingredient need to be formulated as an enteric- ebruary 2006
F coated solid dosage form in which the LMER: lactulose:mannitol urinary excretion ratio; CV = coefficient of variation. Treatments were 0.5g ingredients are gradually co-released as the GIPET I in 15-mL solution administered via perfusion tube to the jejunum in the presence and absence of formulation moves along the epithelium of the 2 g mannitol / 5g lactulose / 9 g glycerol administered as 100-mL solution orally at different time upper small intestine. Therefore, in contrast with intervals. Statistical significance was assessed by paired t-test against group A. Group B was statistically GIPET technology, simple ad-mixing of different from baseline if two high responding outliers were removed from the analysis. Data supplied by solutions of promoters and active agents is Dr. SJ Warrington, Hammersmith Medicines Research, Hammersmith Hospital, London, UK. unlikely to be effective in vivo because co-
Drug Delivery Technology Drug Delivery Technology localized release cannot be guaranteed.
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REFERENCES BIOGRAPHIES
1. Amidon G, Lennernas H, Shah VP, Crison J. A theoretical basis for a biopharmaceutic drug Dr. Thomas W. Leonard, Vice President and CSO at classification: the correlation of in vitro drug Merrion Pharmaceuticals, Inc., has over 23 years experience in product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413-420. pharmaceutical R&D, drug development, formulation, and 2. Tenjarla S. Microemulsions: an overview and manufacturing. He is a graduate of the University of South pharmaceutical applications. Crit Rev Ther Drug Carrier Syst. 1999;16(5):461-521. Carolina School of Pharmacy and earned his PhD in 3. Thanou M, Verhoef JC, Junginger H. Oral drug Pharmaceutics from Virginia Commonwealth University. He has written numerous absorption enhancement by chitosan and its derivatives. Adv Drug Deliv Rev. 2001;52(2): publications and abstracts, and is the inventor of 25 issued and in-process 117-126. patents in drug delivery and female healthcare. 4. Sawada T, Ogawa T, Tomita M, Hayashi, M, Awazu S. Role of paracellular pathway in non-electrolyte permeation across rat colon epithelium enhanced by sodium caprate and sodium caprylate. Pharm Res. 1991;8(11):1365-1371. is the Formulations Group Leader at 5. Anderberg EK, Lindmark T, Artursson P. Sodium Ms. Edel O’Toole caprate elicits dilatations in human intestinal tight Merrion Biopharma Ltd. and has 10 years experience in junctions and enhances drug absorption by the paracellular route. Pharm Res. 1993;10(6):857-864. Formulation and Process Development. Her particular areas of 6. Hall CW. Kirk-Othmer Encyl Chem Tech. 4th ed. interest include controlled release. She is a graduate of the New York, NY: John Wiley and Sons;1995:705. University of London (Greenwich) and Dublin Institute of 7. Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thompson PDR;2005:2049-2057. Technology. Ms. O’Toole is a co-inventor on patents in drug delivery as well as 8. Cramer JA, Amonkar MM, Mayur M, Hebborn A, cosmetic formulations. Altman R. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin. 2005;21(9):1453-1460. 9. Gordon DH. Efficacy and safety of intravenous bisphosphonates for patients with breast cancer Dr. Fiona Brennan, a Formulation Scientist with Merrion metastatic to bone: a review of randomized, double- Biopharma Ltd., is a graduate of Science at University College blind, phase III trials. Clin Breast Cancer. 2005;6(2):125-131. Dublin. She earned her MSc in Medical Genetics at the 10. Merli G. Anticoagulants in the treatment of deep University of Newcastle, UK, and her PhD from the School of vein thrombosis. Am J Med. 2005;118(Suppl 8A):13S-20S. Pharmacy, Trinity College Dublin, where she was a Post- 11. Vavra I, Machova A, Holecek V, Cort JH, Zaoral M, doctoral Fellow in 2004. She has written and co-authored several publications Sorm F. Effect of a synthetic analogue of vasopressin in animals and in patients with diabetes and presentations. insipidus. Lancet. 1968;1(7549):948-952. 12. Hera, 2002. Hera Targeted Risk Assessment of Fatty Acid Salts. June 2002. ol 6 No 2 ol 6 No 13. JECFA,1986. 29th Report of the Joint FAO/WHO V Expert Committee on Food Additives. WHO Dr. David Brayden is a Senior Lecturer and a Principal Technical Report Series No. 733. Investigator at the Conway Institute, University College Dublin, 14. SCF, 1995. Extracts from First Report on Ireland. From 1991-2001 he was a senior scientist at Elan Chemically Defined Flavoring Substances. ebruary 2006
Scientific Committee for Food. Annex 6 to Corporation specializing in oral peptide delivery. He is the F document III/5611/95. author or co-author of 80 research publications and is the 15. Blomquist L, Bark T, Hedenborg G, Norman A. Evaluation of the lactulose/mannitol and 51Cr- current Chairman of the UK-Ireland Chapter of the Controlled Release Society. ethylenediaminetetraacetic acid/14C-mannitol methods for intestinal permeability. Scand J Dr. David Brayden is a consultant to Merrion Biopharma Ltd. Gastroenterol. 1997;32(8):805-812. 16. Widmaier EP, Raff H, Strang KT. In: Vander, Sherman and Luciano’s Human Physiology: The Mechanisms of Body Function. 9th ed. McGraw Drug Delivery Technology Hill Publisher: New York, NY;2004. 47 PRESSURE-SENSITIVE A D H E S I V E S
Silicone Pressure-Sensitive Adhesives Versus Tacky Gels
By: Stephen Bruner and John Freedman
INTRODUCTION
By definition, transdermal, drug delivery To make an educated decision regarding applications mandate the use of adequate adhesive chemistry choices, it’s vital to understand the systems, not only to keep the pharmaceutical differences between silicone PSAs and gels in agent in contact with the intended surface, but both composition and physical performance. After to facilitate sustained, controlled delivery. reviewing supplied forms and basic chemistry, Engineers who determine the optimal silicone NuSil Technology, LLC, compared these factors, chemistry for their devices have a few options. as well as peel and tack data, to illustrate While pressure-sensitive silicone adhesives (PSAs) the strengths, advantages, and disadvantages have typically been considered optimal for of each technology. transdermal applications, silicone gel technology has emerged as an excellent option.
HISTORIC PERSPECTIVE Remover®, Neutrogena’s On-the-Spot biologically inert.2 In addition, silicones Acne Treatment®, and several brands of are ubiquitous in the medical device Since 1979, PSAs have been a the nicotine patch, are examples of how industry in both long-term, implantable mainstay in transdermal, drug delivery. this technology has moved readily into devices, and external devices. Second is PSAs provide pharmaceutical companies direct consumer applications. Estimates the compatibility/permeability of the means to supply a range of active for growth in this area are 12% annually.1 silicones with many pharmaceutical agents in a non-invasive, controlled- Some of the usual adhesives incorporated agents, not just hormones. Other release system, as well as reduce the in transdermal, drug delivery systems are compatible drugs include healthcare industry’s dependence on polyisobutylenes (PIBs), silicones, and antidepressants; anxiolytics; vitamins B6, gastrointestinal and needle-based acrylic-based PSAs. For this article, D, and E; antifungals; opioid and non- administrations. The overriding benefits silicone-based PSAs are used for opioid analgesics; and antiviral ol 6 No 2 ol 6 No V of these systems include improved comparative purposes. compounds.3 patient compliance and steady drug Silicones are good candidates for levels within the bloodstream. transdermal, drug delivery systems
ebruary 2006 Estradiol, testosterone, and because they offer two major benefits to SILOXANE CHEMISTRY F nitroglycerin are just a few of the drug-device developers. First, silicones compounds currently found in prescribed, have a 50-year-plus history in biomedical Silcones’ compatibility and transdermal, drug delivery systems. applications and, in that time, a permeability with pharmaceutical agents Over-the-counter (OTC) products, such considerable body of work has been is a function of the siloxane-based as Dr. Scholl’s Clear Away Wart assembled that characterizes silicones as polymers and resins used to formulate Drug Delivery Technology Drug Delivery Technology
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FIGURE 1 Equation 2. A Divinyl-Terminated, Dimethyl Polysiloxane’s Hydrophobicity is Ideal for the Solubility of Pharmaceutical Agents
the elastomer, hsheath is the thickness of the sheath in cm, and t is the time in days. Determination of these values is aided by additional research in this area that relates the molecular weight and melting point of the drugs to release rates, as well as demonstrates that the addition of fatty acid esters improve release rates of certain drugs.4,6 Silicone polymer chemistry can be modified to include different groups on the these systems, as well as the interaction in silicone elastomers. This free volume and backbone. For example, trifluoropropyl potential created by the siloxane polymer the high compressibility found in silicones methyl dimethyl siloxane copolymers are backbone of repeating silicon and oxygen are associated with their permeability to used in applications in which solvent atoms. The two free pairs of electrons certain gases and liquids. The gas resistance is required, while diphenyl silicone associated with each oxygen atom can form permeability of silicone rubber is up to 100 polymers are used in elastomeric hydrogen bonds with proton donors, often times greater than natural or butyl rubber. formulations, when a high-refractive index is resulting in different degrees of hydrogen In the specific case of drugs or active necessary (intraocular lenses or UV and heat bonding with reinforcing fillers. Despite its pharmaceutical molecules, release rates in protection). The diphenyl and ability to form hydrogen bonds, silicone is silicones are determined by the drug’s trifluoropropylmethyl functionality may also considered hydrophobic in nature. The solubility in a silicone and the diffusion affect drug solubility and, in turn, affect methyl constituency on the siloxane polymer coefficients of those drugs in silicones release rates. The concentration of these backbone creates this effect. A vinyl- through the Higuchi equation4,5 (Equation 1 groups on the backbone can be easily altered terminated, dimethyl polysiloxane can be corresponds to a matrix device, and and optimized for specific compounds. A seen in Figure 1. Equation 2 corresponds to a reservoir divinyl-terminated, This hydrophobicity is ideal for the device). diphenyldimethylpolysiloxane copolymer solubility of pharmaceutical agents having ol 6 No 2 ol 6 No
structure is seen in Figure 2. V mostly non-polar structures. Another Equation 1. characteristic of silicone systems is the large atomic volume of the silicon atom itself, SILICONE PSAS ebruary 2006 which, along with the size and position of F Silicone PSAs incorporate a high- constituent groups, explains the virtually molecular-weight polydimethylsiloxane complete freedom of rotation around the Si- Where Q is the cumulative amount of polymer and a tackifying silicone resin O-Si bond. Silicone polymers form helixes, drug released per device-unit area, A is the dispersed in a solvent system. The solvent and the bond angles of the silicon-oxygen drug loading, Csil is the drug solubility in the provides the system with viscosity control, bonds create large amounts of free volume silicone, Dsil is the diffusivity of the drug in as silicone components are virtually Drug Delivery Technology Drug Delivery Technology
49 PRESSURE-SESSENSITIVNSITIVE A D H E S I V E S
When the adhesive is coated directly onto a Table 1. The tested materials, as well as their material, release film, this is called an unsupported composition, and cure schedule. PSA transfer film. Common post-production processes include die cutting and laser Material Name Material Composition Cure Schedule cutting for later use in component assembly MED-1356 Dimethylpolysiloxane PSA, 37ºC for 30 minutes, and automated pick-and-place solutions for 35% Solids in Ethyl Acetate 150ºC for 90 minutes difficult-to-apply parts and materials.7 MED-1356 Dimethylpolysiloxane PSA, 37ºC for 30 minutes, Silicone PSAs are not without their (peroxide- catalyzed)* 35% Solids in Ethyl Acetate, 150ºC for 90 minutes drawbacks. As stated previously, most PSAs 0.5 pph PD-50S Based on are dispersed in a solvent system to provide Solids viscosity control. The solvent can be MED-6340 Dimethylpolysilixane Gel, 100ºC for 30 minutes problematic and limiting in transdermal 100% solids drug delivery systems. Environmental concerns regarding Volatile Organic GEL-9502-30 Diphenyldimethylpolysiloxane 100ºC for 30 minutes Gel, 100% solids Compounds (VOCs) and plant-safety initiatives are costly factors that must be * MED 1356 product is not supplied as a peroxide-cured product. considered. In addition, solvent systems are dynamic, because evaporating solvent can impossible to process at room temperature 90°C to ensure that the peroxide catalyst impact viscosity, leading to process with standard coating equipment. If does not cure while solvent is present. The variations. PSAs can also limit the containing a catalyst, silicone PSAs temperature is then increased to 130°C to transdermal system design, as these typically crosslink by curing after removing 200°C, although it is more commonly raised materials are typically used in the solvent. Two systems are currently to 350°F maximum because of limitations multilaminate, reservoir designs. PSAs that available: platinum-catalyzed and peroxide- of the coating substrate (ie, shrinkage and utilize peroxide systems, as mentioned catalyzed. stretching), eliminating the peroxide previously, require an elevated temperature Platinum-catalyzed systems are through decomposition. A high-crosslink- and may negatively impact active agents. common in PSAs and utilize vinyl- density PSA can be better achieved through This limitation may require that the PSA is functional polymers, such as in Figures 1 & peroxide curing due to the ability to processed in a separate step. 2, and hydride-functional crosslinking increase peroxide levels to 4%. polymers to cure in the presence of the Converters of tape and adhesive-backed catalyst. Curing of these PSAs is achieved components take the liquid PSA and either SILICONE GEL TECHNOLOGY through multi-zone ovens. The solvent is wet coat in sheet form, for small ol 6 No 2 ol 6 No V eliminated by a gradual increase in applications, or in roll form (pilot coaters Silicone gels share the same basic temperature from 60°C to 90°C. and full-width production coaters), when siloxane polymer chemistry as silicone Peroxide-cure systems employ benzoyl large quantities are required. The PSA may PSAs but lack the silicone resin credited ebruary 2006 F peroxide, or 2,4-dichlorobenzoyl peroxide, be applied on one or both sides of a with supplying adhesive strength to the ® ® as a catalyst to drive a free-radical reaction substrate, such as Kapton , Mylar , system. Silicone gels are typically ® and achieve cure. Curing is normally Nomex , foils, foams, and rubbers, or it can composed of two types of siloxane performed in a multi-zoned oven. Solvent be coated directly onto a release film. Coat polymers: vinyl-functional polysiloxanes removal is achieved through a gradual weights on supported film range in and hydride-functional polysiloxanes. increase in temperature, starting at 60°C to thickness from 0.0003” to more than 0.010”. Silicone gels are low-viscosity materials Drug Delivery Technology Drug Delivery Technology
50 PRESSURE-SESSENSITIVNSITIVE A D H E S I V E S
FIGURE 2 authors and are important to the discussion. The two properties tested in this study were A Divinyl-Terminated Diphenyldimethyl Polysiloxane Structure can be Easily 90-degree peel strength (NuSil Technology Altered & Optimized for Specific Compounds Test Method TM087 Reference ASTM D1876) and tack testing (NuSil Technology Test Method TM103 Reference ASTM D429 Method D).8 Because pressure- sensitive system properties are influenced by the thickness or amount of adhesive, care was taken to ensure identical amounts of silicone were used. The materials were prepared per the applicable test method and specific material cure recommendations. Four materials were tested, and Table 1 describes the material and characteristics. The testing was performed in triplicate for that are not dispersed in solvent systems. be utilized in multilaminate, reservoir each material, results appear in Table 2. These materials do not contain reinforcing or monolayer drug-in-adhesive delivery fillers, such as silica or silicone resins, systems. found in silicone elastomer systems. As a CONCLUSIONS & result, they offer little tensile or tear OBSERVATIONS strength but are extremely soft and COMPARATIVE compliant. Typically, gels used in thin-film ADHESIVE PROPERTIES The discussion and data presented applications use reinforcing fabrics to add provide transdermal drug delivery system strength. designers with another choice in pressure- The aforementioned discussion The tack and adhesion of silicone gels sensitive-type, silicone-based adhesives. provides some basic differences between Silicones’ historic healthcare use and drug have been proven in several transdermal, silicone PSAs and gels—from chemistry to solubility make both silicone PSAs and adhesive-type applications. The testing supplied forms. The following data was tacky gels good candidates for certain drug discussed later in this article illustrates the compiled to determine the key property delivery applications. From the data, it is superior tack properties of silicone gels differences between silicone PSAs and gels apparent silicone gels offer higher tack, but compared to silicone PSAs. Pfizer’s Scar (and differences in silicone gels with lower peel strength, than PSAs. It can also ®
Solution and Smith & Nephew’s Cica 2 ol 6 No dissimilar compositions). The study be concluded that gels containing phenyl V Care® are OTC examples of silicone gels functionality provided higher tack and peel acknowledges that other silicone used in transdermal applications to treat results than the dimethyl gel. When manufacturers produce PSAs and gel hypertrophic and keliod scarring. considering these results, alongside factors
technology, but the purpose of the results ebruary 2006 Silicone gels cure in the presence of such as drug-release rates, VOC F further on is to demonstrate the differences platinum catalysts to solid forms that do elimination, and reservoir/matrix delivery between NuSil’s current technology not flow. Gels can be formulated to cure at designs, it is clear that, no matter which offerings. In addition, the formulation low temperatures, which may be ideal for chemistry you choose, tradeoffs must be compositions of the tested materials as expected. pharmaceutical agents that are unstable at previously described are known to the higher temperatures. These materials can Drug Delivery Technology Drug Delivery Technology
51 PRESSURE-SESSENSITIVNSITIVE A D H E S I V E S
BIOGRAPHIES Table 2. Test Results.
Material Peel Peel Surface Surface Name Strength Strength Tack Mean Tack Mean Standard (psi) Standard (lbf/in) Deviation Deviation (lbf/in) (psi)
MED-1356 14.7 0.1 2.5 0.8
MED-1356 4.4 0.3 3.4 1.1 (peroxide-catalyzed)* Mr. Stephen Bruner is the MED-6340 1.3 0.0 5.0 2.1 Marketing Director at NuSil GEL-9502-30 1.4 0.2 8.2 2.5 Technology LLC. He earned his BA in Chemistry from the University * MED-1356 product is not supplied as a peroxide-cured product of Colorado and his MBA from Pepperdine University.
ACKNOWLEDGEMENTS 3. Nabahi and Shorhre. US Patent No. 6,039,968 (March 21, 2000).
The authors would like to thank Susan 4. Malcolm K. Woolfson D, Russell J, Tallon P, Rhodes of The University of Akron, Dept. McAuley L, Craig D. Influence of silicone of Polymer Science, for her content elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal contributions and expertise in PSA rings. J Controlled Release. 2003;90:217- technology, Jim Lambert for his research 225. contributions, and NuSil Technology LLC’s technical healthcare group and commercial 5. Mojtaba ST, Mashak A, Jamshidi A, Imani M. Study of progesterone release testing services for their work. mechanisms from a silicone matrix by a new analytical method. J Appl Polymer Sci. 2004;91:3040-3044. Mr. John Freedman is a REFERENCES Technical Sales Representative
ol 6 No 2 ol 6 No 6. Nabahi and Shorhre. US Patent No. V 5,788,980 (August 4, 1998). responsible for ingestible silicones 1. Townsend FL. Adhesives in transdermal for pharmaceutical use. He has 7 drug delivery systems. Article posted 7. Reigler B, Meyer J. Low outgas pressure- 11/01/05 at sensitive adhesives for aerospace years of experience with silicones,
ebruary 2006 www.adhesivesmag.com/CDA/ArticleInform applications. Paper presented at SAMPE
F specializing in mechanical testing. ation/features/BNP_Features_Item. Conference, June 2004, NuSil Technology.
2. Noll W. Chemistry and Technology of 8. NuSil Technology’s Test Methods are Silicones. Academic Press: New York, available by request at www.nusil.com NY;1968. Drug Delivery Technology Drug Delivery Technology
52 SUSTAINED R E L E A S E pH- Independent Release From Verapamil Hydrochloride-Coated Tablets By: Munish Kumar Dhiman, MPharm; Amit Chivate, MPharm; and S.S.Poddar, PhD
ABSTRACT
Weakly basic drugs or their salts demonstrate by coating of tablets with polymethacrylates. pH-dependent solubility. Thus, release from oral Presence of organic acid within the tablet was solid dosages decreases with increasing pH-milieu found to maintain low pH values during drug of the gastrointestinal tract. The aim of this study release in pH 1.2 as well as pH 6.8 media, resulting was to overcome this problem and to achieve pH- in pH-independent in vitro release of the model independent release of verapamil HCl from tablets. drug. Quantity of succinic acid, coat formulation, The approach used here to solve the problem of pH- and proportion were optimized for the desirable dependent release of a weakly basic drug was the drug release. inclusion of succinic acid to tableting core followed
INTRODUCTION acids, when the pka value of the weakly obtained from SD Fine Chemicals, Mumbai. basic drug or the pH value at which Microcrystalline cellulose (Vivacel-101®) Chronic illness is often treated with precipitation occurs would be exceeded by was obtained from J. Rettenmaier & Sohme medication that involves multiple daily the pH of intestinal fluids, precipitation of Gmbh. Magnesium stearate, was obtained doses, sometimes exceeding three times a the drug would take place within the dosage from Research Lab Chemical Corporation, day for a relatively prolonged duration. form. Precipitated drug being no longer Mumbai. The other ingredients utilized were Patient compliance, and therefore efficacy of capable of release, its therapeutic efficacy of analytical grade. therapy, might be improved by the use of an would be doubtful.3 By maintaining a low extended-release formulation.1 pH value within the core, a constant drug Solubility Determination Many drugs are weak bases or salts release can be achieved over a wide pH Solubility of VHC in different pH thereof and thus demonstrate pH-dependent range of gastrointestinal milieu.3 Two ranges has been documented, which is >150 solubility in the pH range available in important versions are matrix and coated mg/ml at pH 1.2 and 2.7 mg/ml at pH 6.8.2 gastrointestinal tract. At the low pH found in units. Not much work has been reported on Solubility of succinic acid at 37°C was the stomach, weakly basic drugs are freely the coated type. Thus, the objective of the determined gravimetrically, which was soluble resulting in higher dissolution rates. present work was to achieve a pH- found to be 58 mg/ml at pH 1.2 and 107 ol 6 No 2 ol 6 No
However, this rate decreases and sometimes independent sustained release of a weakly mg/ml at pH 6.8. V even significantly when the dosage form has basic drug, verapamil hydrochloride (VHC), been transferred to the high pH region of the in association with succinic acid (SA) from Tablet Preparation small intestine. With usual sustained-release release-retard polymer-coated tablets. Tablets containing 120 mg VHC ebruary 2006
(SR) dosage forms, a possible pH-dependent (batch size, 250 tablets) were prepared F release could result in in vivo variability and MATERIALS & METHODS using microcrystalline cellulose (MCC) and bioavailability problems.2 SA by direct compression (DC) (Table1). Therefore, the use of pH adjusters, ie, Verapamil hydrochloride was obtained Methyl red was included to monitor the organic acids of sufficiently low pka values, from Nicholas Piramal India Ltd., Mumbai. microenvironment pH. Hardness was kept have been described by many authors for the Eudragit RSPO and Eudragit RLPO were at 6 kg/cm2. Compression was carried out design of SR formulations due to their gifted by Degussa Pharma Polymers, on a 10-station rotary machine (Jaguar, ability to create an acidic microenvironment Germany. Polyethylene glycol 4000 (PEG General Machinery Co., Mumbai) with Drug Delivery Technology 2-5 4000), triethyl citrate, and succinic acid were inside the dosage form. Without such 9-mm standard concave punches. 53 SUSTAINED R E L E A S E
FIGURE 1 FIGURE 2 Drug Release From Coated VHC Tablets Without Succinic Acid Influence of Ratio of Succinic Acid: Verapamil HCl on Release of Drug From 5.8% Film-Coated Tablets (Eudragit RSPO: Eudragit RLPO, 9:1) With 11% PEG-4000 as Plasticizer
studying their properties (visual appearance Table 1. Formulation of Tablets and mechanical strength). To study mechanical strength varying quantity of water was used to provide a range Batch No. & Composition (%) of downward breaking pull on the clamped Component film samples. The value at the break point was indicative of the mechanical strength of V1 V2 V3 the films. 7 Coating levels were represented as Verapamil HCl (Drug) 30.0 30.0 30.0 percent weight gain due to coat deposition on the tablets. Aliquots of tablets were taken out MCC (Excipient) 57.5 51.5 45.5 to represent a percent weight rise, while the coating progressed. The tablets were always Succinic acid (pH-adjuster) 12.0 18.0 24.0 dried for at least 5 min in the pan after spraying had been completed, before taking
ol 6 No 2 ol 6 No any samples or emptying the coating pan. V Magnesium stearate 0.5 0.5 0.5 Such withdrawn samples or batches were dried to a constant weight in a hot air oven for V – Succinic Acid:Drug = 0.4:1; V – Succinic Acid:Drug = 0.6:1; V – Succinic Acid:Drug = 0.8:1 1 2 3 about 1 h at 45°C. Table 2 provides the various parameters for the coated tablets. ebruary 2006 F (Eudragit RSPO) and polymethacrylate Coating mixtures (Eudragit RSPO & Eudragit RLPO Dissolution Testing Tablets (batch size, 200 tablets) were in various ratios) in isopropyl alcohol were In vitro dissolution performances of film coated in a 5-inch coating pan (Erweka) used as film formers. PEG 4000 and triethyl formulations were monitored in a 900-ml by atomizing the coat solution (Spray gun 100 citrate were included as plasticizers. The medium using a USP type 2 apparatus at 50 ml S 68; Pilot) at 10-psi pressure. Pan speed film composition was optimized by casting rpm at 37°C ± 0.5°C.7 The media used were of
Drug Delivery Technology Drug Delivery Technology was kept at 25 rpm. Polymethacrylate free films on a Teflon plate and then pH 1.2 (0.1 N HCl) and pH 6.8 (phosphate 54 SUSTAINED R E L E A S E
FIGURE 3 FIGURE 4 Dependence of Release of Verapamil HCl on Effect of Plasticizer on Release From Coat Proportion in Tablets Coated Tablets (5.8% coat, RSPO:RLPO, 9:1)
Table 2. Physical Parameters for Coated Tablets
Batch No. Sr. No. Test V1 V2 V3 1. Hardness (kg/cm2) (±SEM) 6-7 (±0.5) 6-7 (±0.5) 6-7 (±0.5)
2. Thickness(mm) (±SEM) 2.25 (±0.3) 2.27 (±0.4) 2.26 (±0.4)
3. % Weight rise (±SEM) 5.65 (± 0.03) 5.69 (±0.06) 5.67 (± 0.06)
4. Tablet weight (mg) (Average ±SEM) 386 (±5.3) 384 (±6.2) 385 (±5.9)
5. Assay (%) (±SEM) 101.32 (±1.21) 100.82 (±1.92) 98.35 (± 2.10) ol 6 No 2 ol 6 No *Mean of 6 readings (n=6), # SEM-Standard Error Mean V
buffer). Drug-release studies were performed medium at the same temperature. Analysis RESULTS & DISCUSSION ebruary 2006 for the first 2 h in pH 1.2 medium and for the of the dissolved drug in both the media F next 8 h at pH 6.8. The speed of the paddle was carried out via UV spectrophotometry Figure 1 shows drug release from was set at 50 rpm. Exactly 10-ml aliquots of at 278 nm against the appropriate blank. coated VHC tablets without organic acid samples were withdrawn at 15, 30, and 60 The concentration of drug was calculated (succinic acid). Organic acid (SA) was used min, followed by an hourly interval for the from the standard plots of drug in a in an attempt to match the release rate of the next 9 h. Each aliquot withdrawal was pH 1.2 medium and pH 6.8 phosphate weakly basic drug in pH 6.8 phosphate
followed by replenishment with 10 ml of the buffer, respectively. buffer with the release rate in pH 1.2 (0.1 N Drug Delivery Technology
55 SUSTAINED R E L E A S E
FIGURE 5 FIGURE 6 Image of Coated Tablet Image of Coated Tablet After 2 Hours in pH 6.8 After 8 Hours in pH 6.8 Phosphate Buffer Phosphate Buffer
Table 3. Mechanical Strength of Free Films contents; the indicator shows color change in the same pH around which solubility of Sr. No. Formulation Code Plasticizer (%) Mechanical Strength(g) VHC declines. The experiments showed that the tablet core remained red (low pH), 1. F – 1 10 182 (±3.4) although the color of the outer portion of the tablet slowly turned to pink (high pH 2. F – 2 11 206 (±2.9) but still below 5.8). Even at the end of 10 h, ie, 8 h stay at pH 6.8, there was retention of the pink color of the tablet, indicating 3. F – 3 12 165 (±4.2) the presence of adequate acidic microenvironment. Thus, the pH within the *Mean of 6 readings (n=6), # SEM- Standard Error Mean core of the coated tablets remained acidic, maintaining the condition conducive for HCl) ( Figure 2 ). The pH-independent acidic and thus the solubility of weakly solubilization and release of the drug. profiles shown in Figure 2 were obtainable basic drug to be high. Organic acids have In the absence of a pH adjuster, as the for VHC. This refers particularly to the relatively low solubility in lower pH values pH within the tablet would rise, the solubility of VHC would fall, providing ol 6 No 2 ol 6 No total release after 10 h, by which time SA (eg, pH 1.2) than in higher pH values (eg, V caused the release of almost 100% of the pH 6.8).2 Therefore, for further a reducing concentration gradient to act incorporated drug. investigation of the microenvironment pH, as a drive for the outward diffusion of This could be due to the creation of the the pH-indicator methyl red (0.2% w/w) the drug. Thus, eventually the release rate consistent acidic microenvironment inside was included in the tablet formulation to would fall. Construction of a suitable ebruary 2006 F the tablets. Ideally, this acid should dissolve visually monitor the pH within the tablets acidic microenvironment prevented this. gradually to remain within the tablet during during the time span of drug release. The The drug-release profile from the coated the entire period of proposed drug release. indicator is red in acidic pH and yellow for tablets with a composition the same as Independent of the pH value of the pH values above 5.8.2 VHC is soluble below batch V2 but containing no succinic acid dissolution medium, the pH in the tablet pH 5.8. Thus, moving from pH values is shown in Figure 1. There is a 20% core (inside the coat) was expected to be corresponding with gastric to intestinal release of VHC in the first 2 h, which Drug Delivery Technology Drug Delivery Technology
56 SUSTAINED R E L E A S E
FIGURE 7 FIGURE 8 TS Image of Coated Tablet After 2 TS Image of Coated Tablet Hours in pH 6.8 Phosphate Buffer After 8 Hours in pH 6.8 Phosphate Buffer
declines as the time progresses, and only considered to be optimum for an effective dissolution. Thus, 3.5% weight rise tablets 50% VHC is released in 10 h. constant release of VHC. showed mechanical failure of the coat after 5 To assess the effect of the amount of No doubt that SA also gets transported to 6 h during dissolution. Coating to a SA on the release properties of VHC from out of the tablet, as does the VHC. Thus, percent rise higher than 5.8% resulted in an diffusion tablets, the proportion of SA to there are chances of SA getting depleted unacceptably low release rate. With a 5.5% VHC was varied. As shown in Figure 2 before the full exit of VHC. Increasing coat weight rise, there was more of a burst (keeping the thickness of the coating of thickness may push up the drug-release release in the initial 1 h than with a 5.8% tablets the same), the effect on release was retardation beyond acceptable limits. Thus, weight rise. The 5.8% weight rise with dependent on the ratio of SA and active adding an adequately high quantity of SA in Eudragit RSPO gave a release of nearly 40% ingredient. the tablets was the solution. It was clear drug in 10 h. While a mixture of Eudragit As illustrated in Table 1, SA and VHC (Figure 2) that by varying the proportion of RSPO and Eudragit RLPO in the 9:1 ratio as have been tried in different proportions in SA and VHC, there was a profound effect on 5.8% coat gave the release rate of 10% per h the formulations. An SA:VHC ratio higher the release rate. as shown in Figure 3. than 0.8:1 led to compression and coating Because the release of drug through The aforementioned change in the difficulties, while lowering this ratio below slightly swellable but insoluble release rate of tablets coated with a mixture 0.4:1 could not achieve sufficient pH- polymethacrylic acid copolymers of Eudragit RSPO and Eudragit RLPO (9:1) independent release profiles. An SA:VHC (polymethacrylates) involves the diffusion of in comparison to the Eudragit RSPO-coated ratio of 0.4:1 (V1) resulted in a decreased dissolved substance through the membrane, tablets indicates the effect of a high
release rate as only 55% drug was released the coat membrane thickness would exert an permeability polymer (Eudragit RLPO) on 2 ol 6 No V in 10 h, while formulation with the ratio of effect on the rate of passage of VHC. release rate. Eudragit RSPO has lower 0.8: 1 (V3) released drug at a slightly lower Various coating levels of Eudragit permeability, and Eudragit RLPO has higher rate than 0.6: 1 (V2), where 92% of drug RSPO have been tried, which included 3.5%, permeability, so a mixture of Eudragit RSPO was released in 10 h. This might be due to 4.5%, 5.5%, 5.8%, and 6.0%. Coat and Eudragit RLPO could be used to achieve ebruary 2006 the reason that as succinic acid amount was composition of polymethacrylates included the desired release rate. Thus, using Eudragit F increased, the MCC amount had to be Eudragit RSPO and 11% PEG 4000 in RSPO and Eudragit RLPO in the ratio of 9:1 reduced, which lead to less swelling of the isopropyl alcohol. Coating to a lower percent with a weight rise due to coating of 5.8 % tablets. An SA:VHC ratio in proportion of weight rise resulted in improper coating gave the desired release rate. 0.6:1 resulted in a release rate of about 10% (indicated by non-uniform distribution of With PEG 4000, at a concentration of per h for 10 h. Thus, this composition was coat), and there was also coat failure during 11% in the coat (Eudragit RSPO:Eudragit Drug Delivery Technology Drug Delivery Technology
57 SUSTAINED R E L E A S E
Dissolution of VHC out of the Eudragit Table 3. Mechanical Strength of Free Films RSPO and Eudragit RLPO mixture-coated tablets is best described by a zero-order kinetic Sr. No. Formulation Code Plasticizer (%) Mechanical Strength(g) for the batch V2 at a 5.8% coat level. The batch V1 of the same coating level showed a 1. F – 1 10 182 (±3.4) best fit for first-order kinetic model as shown in Table 4. The percentage deviation from a 2. F – 2 11 206 (±2.9) zero-order release profile was minimum for V2 as compared to V1 and V3 (Table 5). The 3. F – 3 12 165 (±4.2) studies indicated there was creation and maintenance of an acidic microenvironment by *Mean of 6 readings (n=6), # SEM- Standard Error Mean organic acids, ie, SA, for which the support was provided by the use of methyl red. Figure 5 shows a coated tablet after 2 h in pH 6.8 phosphate buffer, showing the red color Table 4. Model Fits for Different Succinic Acid: Verapamil HCL of the tablet. There was a slight color change Ratio Batches Coated with Eudragit-RSPO and RLPO (9:1) noticed in the tablets at the end of 8 h in pH 6.8 buffer, ie, red to pink. This may be due to a fall in indicator strength due to leaching (Figure 6). r2 Batch To study further, the mechanism of No. maintenance of acidic microenvironment inside Zero-Order Kinetics First-Order Kinetics the tablets transverse sections (TS) of tablets were taken (Figures 7 & 8), showing red color and hence sufficient acid inside the core. There V 1 0.9894 0.9949 was no color change from red to yellow, V 0.9992 0.7023 indicating that there was sufficient SA present 2 inside the tablet core and hence maintenance of high drug solubility even after a transition from V 0.9982 0.8685 3 pH 1.2 to 6.8 as dissolution progressed.
2 r – correlation coefficient of regression lines; V1 – Succinic Acid:Drug = 0.4:1; CONCLUSION V2 – Succinic Acid:Drug = 0.6:1; V3 – Succinic Acid: Drug = 0.8:1
The formulation of coated tablets for pH- RLPO = 9:1), and coat itself at 5.8%, it was it has been found that there was a independent release of VHC was successfully possible to achieve a constant release rate for considerable decrease in release rate as only carried out. Succinic acid:VHC in ratio 0.6:1 ol 6 No 2 ol 6 No V 10 h as shown in Figure 4. At this plasticizer 85% of drug was released in 10 h. This and coating level of 5.8% w/w of Eudragit- concentration, the tablets maintained their might be due to the better pore-forming RSPO and RLPO (9:1) produced the pH- integrity in spite of noticeable swelling during nature of PEG 4000. independent release profiles. Support for dissolution. A plasticizer concentration below To get an insight into the release creation of an acidic microenvironment inside ebruary 2006 F 11% of polymer content could not maintain mechanism for coated tablets with different the tablets was provided through the desired film strength, while a ratios of SA:VHC, the dissolution profiles the use of the indicator methyl red. The concentration above 11% resulted in inferior were plotted in various standard manners, and formulations prepared now require animal mechanical attributes as shown by studies on regression analysis was performed for each. studies for further investigations. Thus, it could free films (Table 3). Best fits were calculated on the basis of the be concluded that Eudragit-coated tablets with Upon changing the plasticizer from correlation coefficients (r2) determined for an acidic microenvironment using SA Drug Delivery Technology Drug Delivery Technology PEG 4000 (11%) to triethyl citrate (10%) each of the graphical treatments and demonstrated a pH-independent release profile 58 that was optimized by free-film cast studies, percentage deviation from zero-order release.8 from the tablets. SUSTAINED R E L E A S E
BIOGRAPHIES Table 5. Percentage Deviation From Ideal Zero-Order Release Profile Dr. S.S. Poddar is currently working % Deviation From Ideal Zero-Order Release Profile as an Assistant Time (Hours) Professor of V1 V2 V3 Pharmaceutics at K.M. Kundnani 0 0 0 0 College of Pharmacy, Mumbai, India. With more than 25 years of academic 1 10.00 10.00 0 experience, he has 25 publications and more than 100 presentations to 2 0 0 10.00 his credit. He earned his MPharm and PhD in Pharmaceutics from the 3 14.00 0 8.00 University of Mumbai, Mumbai 4 24.28 4.28 1.45 (India). His research interests include designing pharmaceutical dosage 5 28.88 1.10 2.25 forms, including novel methods for modified release. He is acting as a 6 31.81 0.90 4.54 technical advisor to various pharmaceutical companies for the 7 33.84 1.54 6.15 development of novel formulations, scale-up, and process optimization. 8 34.00 2.00 7.33
9 35.88 1.76 8.25 Mr. Munish Kumar is a 10 38.94 2.63 9.47 Research Scholar in the Pharmacy ACKNOWLEDGEMENTS 3. Thoma K, Zimmer T. Retardation of weakly Department at The basic drugs with diffusion tablets. Int J Pharm. M.S. University of 1990;58:197-202. The authors wish to acknowledge Mr. Baroda. He earneed his MPharm from Dilip Swain from Degussa Pharma Polymers 4. Timko RJ, Lordi NG. In vitro evaluation of three the University of Mumbai, Mumbai commercial sustained-release papaverine Ltd., Mumbai for the free gift samples of hydrochloride products. J Pharm Sci. (India) in 2003. His area of research polymers. They also wish to thank Nicholas 1978;67:496-500. focuses on the design and Piramal India Ltd. for the gift sample of drug 5. Thoma K, Ziegher I. The pH-independent release development of novel drug delivery and J. Rettenmaier & Sohme Gmbh for the gift of fenoldopam from pellets with insoluble film systems. coats. 1998;46:105-113. 2 ol 6 No
Eur J Pharm Biopharm. V samples of MCC. Mr. Munish Dhiman would also like to thank the AICTE, Delhi for 6. Chang ZL. Verapamil. In: Flory KF, ed. Analytical Profiles of Drug Substances. Vol 17. Mr. Amit financial assistance with this study. Academic Press, Inc.: London, UK. 1988;643- 674. Chivate is
working as ebruary 2006 REFERENCES 7. Mishra B et al. Design, development, and F biopharmaceutical properties of buccoadhesive Assistant Manager compacts of pentazocine. Drug Dev Ind Pharm. at Nicholas Piramal 1. Timmins P, Delargy AM, Howard JR. 1999;25:701-709. Optimization and characterization of a pH- India Ltd, NDDS independent extended-release hydrophilic matrix 8. Gohel MC, Panchal MK. A novel mathematical division at Goregaon, Mumbai. He tablet. Pharm Dev Technol. 1997;2:25-31. model for quantitative expression from zero- order drug release. Pharm Tech. 2001;25:62-72. earned his MPharm from the 2. Streubel A, Siepmann J, Dashevsky A, Bodmeier University of Mumbai, Mumbai R. pH-independent release of a weakly basic 9. United State Pharmacopoiea 25/ National drug from water insoluble and soluble matrix Formulary 20, US Pharmacopoieal Convention (India). Drug Delivery Technology tablets. J Control Release. 2000;67:101-110. Inc. Rockville, MD;(2002),2579. 59 Cardinal Health: Improving Quality & Efficiency in Healthcare
ardinal Health is the leading provider of products and services supporting the healthcare industry. The Dublin, Ohio, based CCmultinational develops, manufactures, packages, and markets products for patient care; develops drug delivery technologies; distributes MR. THOMAS STUART pharmaceuticals, medical-surgical, and laboratory supplies; and offers President, Oral Technologies, Pharmaceutical consulting and other services that improve quality and efficiency in healthcare. Technologies & Services segment Employing more than 55,000 people on 6 continents, Cardinal Health produces CARDINAL HEALTH annual revenues exceeding $75 billion. Drug Delivery Technology talked with “One example Thomas Stuart, President of Oral Technologies for Cardinal Health’s of this change - extending the Pharmaceutical Technologies and Services segment, to find out more about life cycle of a drug by Cardinal Health’s drug delivery capabilities and get his perspective on the launching a bioequivalent future of drug delivery. differentiated dose form - is far less likely to succeed in Q: Describe Cardinal Health’s Cardinal Health is the number one provider the future. drug delivery business and the of prescription softgel capsules in the world. We We believe technologies you offer? offer a range of softgel options, including a that critical recently launched plant-based product called
ol 6 No 2 ol 6 No stakeholders ® V A: Cardinal Health is the leading global provider Vegicaps Soft™. Our other proprietary drug like the payor, of drug delivery technologies by nearly every delivery systems include Zydis®, the gold standard physicians, measure. We offer a broad range of both for fast dissolve, and a range of modified-release regulatory traditional and proprietary drug delivery technologies, including EnSolv™, EnCirc™,
ebruary 2006 bodies, patients, F technologies for practically every route of EnVel™, and EnGel™. and even (for administration, including oral, injectable, We also offer electrostatic tablet-coating OTC) retailers respiratory, ophthalmic, and topical. We develop technology through our relationship with Phoqus are expecting solutions for our customers’ Pharmaceuticals, a U.K. pharmaceutical company. better patient formulation/manufacturing problems. We also The Phoqus technology can be employed to outcomes through provide innovative, physician- and patient- modify a drug’s release profile, and provide a Drug Delivery Technology Drug Delivery Technology meaningful preferred dosage forms, which can clinically or unique tablet appearance for anti-counterfeiting commercially enhance our customers’ products. and product differentiation, among other things. 60 innovation.” Our topical technologies include reliably administer a drug. For stakeholder that drives prescribing DelPouch®, which delivers single example, one of our customers behavior. From physicians to retail doses of lotions, creams, or combined Zydis® with an innovative pharmacists and from hospitals to ointments, and Microsponge®, which drug for schizophrenic patients. payors, Cardinal Health participates delivers active ingredients in a Their research showed that not only in nearly every sector of healthcare. sustained manner over time to reduce did the Zydis® version help bring the And we work very hard to use those skin irritation. patients into better compliance, it relationships to generate new value In addition to these, we also also made them more compliant for our customers. For example, we offer more traditional controlled- with other, non-Zydis® format drugs have conducted surveys of both release formulations and clinical and as well. retail pharmacists and physician commercial supply of nearly every We have also gained great customers of Cardinal Health to type of dose form on the market insight into the role that compliance- determine their preferences as to today. enhancing packaging plays in dose form, and the impact those improving patient outcomes. We preferences have on prescribing believe there are currently unmet behavior. We have also made it clinical needs that would be better easier for our customers to secure Q: What are your newest met by combining our advanced comparator drugs for head-to-head technologies and how have delivery technologies with our clinical trials. they changed your drug market-leading packaging. Our Cardinal Health’s overall delivery business? DelPouch® unit-dose topical delivery financial strength and stability also technology is a good example of the give us the resources to invest in A: We are focused on developing intersection of drug delivery and current and new drug delivery innovative solutions to complex packaging. technologies and related capabilities problems and filling unmet clinical and capacity to meet the present and and commercial needs. A good future demands of our customers ® example is the Vegicaps Soft™ and their markets. technology, a plant-derived softgel Q: What are the advantages launched as an alternative to of doing business with traditional softgels. With Vegicaps® Cardinal Health? Soft™, product marketers can Q: What’s different about extend a preferred patient and A: We are passionate about the drug delivery today as physician form to new patient pharmaceutical business and compared to when you populations who have religious, understand that each of our started in the business dietary, or cultural preferences. The customers is unique with different in 1990? product has been successful in the needs. Cardinal Health can support a vitamin, mineral, and dietary customer’s entire range of needs, A: What’s most different is the supplement business, and we expect from drug discovery to commercial level of increased pharmaceutical ol 6 No 2 ol 6 No that it will gain further ground in the manufacturing to sales and market complexity and competition. V pharmaceutical market in the near marketing. We partner with Driven by ever-changing regulatory future. hundreds of companies in the requirements, the growing pressure Our Zydis® fast-dissolve from payors and more difficult drug pharmaceutical industry, including ebruary 2006 F technology is the number one both large, established companies development hurdles in general, our prescription oral fast-dissolve tablet and emerging virtuals. customers have to work harder than technology on the market. Zydis® In addition to the breadth and ever to achieve success. We are helps patients take medication easily maturity of our delivery technology keenly aware that customers’ and quickly, and can also be used to portfolio, we bring to our customers product portfolios require a stream provide efficacy enhancements, such something unique in the drug of continuous innovation to remain as faster onset. For some patients, delivery industry—unmatched relevant and grow. That’s why we Drug Delivery Technology it’s proven to be the best way to insight into essentially every work closely to understand the 61 complete market environment in coupled with sufficient capability systems, and co-market these in which our partners compete, so we and capacity bandwidth to support major worldwide markets. We can best address their needs. both the drug delivery and the believe these technologies will play One example of this change— specialty pharma businesses, this an important role in meeting the extending the life cycle of a drug by can compromise the value of the industry’s need for anti- launching a bioequivalent delivery technology to third parties. counterfeiting solutions and differentiated dose form—is far less It can also create potential conflict improved branding of oral likely to succeed in the future. We of interest situations, where the medications. believe that critical stakeholders like needs of an external partner might As I discussed earlier, the the payor, physicians, regulatory collide with those of an internal fundamental shift in the balance of bodies, patients, and even (for OTC) development program. power toward payors in the United retailers are expecting better patient States, given a boost recently by the outcomes through meaningful launch of the Medicare Part D innovation. outpatient drug benefit in January, Q: Describe the future Nowadays, companies interested will put increased pressure on the of the drug delivery in pursuing a line extension must developers and marketers of drugs technology business and the look for a therapeutic edge or to show – and prove – improved improved convenience leading to role Cardinal Health will outcomes for patients. This will enhanced compliance or outcomes to play in it? impact nearly every part of the differentiate their product. Our work industry, including drug delivery. ® ® A: Technological obsolescence and with Wyeth on Advil Liqui-Gels is We believe Cardinal Health is well competition can make this a a good example of how a drug form positioned here – our delivery difficult business to operate in long can add value to the patient while technologies have a proven track term. These factors have shaped our strengthening the commercial value industry, and will continue to do so record of improving outcomes, and of the brand in the marketplace. The in the future. To stay competitive, studies show both physician and increased solubility from our companies have to innovate patient preference for fast- formulation technology was shown constantly and that takes resources. dissolving and softgel capsule in studies to deliver faster pain relief Like many other industries, these forms. than competing tablet products. factors will likely lead to When you combine our Through advertising and promotion continuing consolidation – perhaps technology, capabilities, and of this outcome difference, Wyeth even accelerating in the near term. capacity edge with the knowledge, effectively has translated a clinical We’ll also see more
ol 6 No 2 ol 6 No insights, and resources across the V benefit into a meaningful point of cooperation between technology whole range of healthcare that we differentiation in arguably one of the providers. A good example is our bring to the table for our customers, most competitive OTC markets. strategic licensing agreement with I believe we will be the partner of ebruary 2006 F We are also seeing many more Phoqus Pharmaceuticals. We choice in drug delivery throughout drug delivery companies seeking to provide commercial contract the next decade. ♦ evolve into specialty pharmaceutical manufacturing services for Phoqus' companies—with mixed results. proprietary electrostatic tablet- Unless you have robust technology coating process and delivery Drug Delivery Technology Drug Delivery Technology
62 POLYMERS & DELIVERY TECHNOLOGIES GEL MATRIX ADHESIVE TECHNOLOGY
Pharma Polymers is one of the world leaders in the manufacturing and Conventional transdermal technology has relied upon traditional supplying of functional coatings for the pharmaceutical industry. pressure-sensitive adhesives, which include primarily acrylate-, EUDRAGIT® polymers are ideal for Enteric Delivery, Controlled Release, silicone-, and rubber- or polyisobutylene- based polymers, as the and Protective Coatings. Based on more than 50 years of experience in primary matrix to adhere the patch to the skin. With these traditional EUDRAGIT® polymer design and formulation know-how for pharmaceutical adhesive types, a significant amount of stratum corneum cells are applications, Pharma Polymers has developed intellectual property on removed and transferred to the adhesive surface, resulting in damage advanced oral drug delivery technologies. The different brands of and irritation to the skin. The technology employed by Aveva and Nitto EUDRAPULSE™, EUDRACOLT™, and EUDRAMODE™ are the Denko is based upon a proprietary adhesive composition that addresses achievements of this intensive research and development effort so far. these issues. This Gel-Matrix adhesive has unusual properties that Pharma Polymers’ business models for commercialization of these drug allow for exceptional adhesion and wear to the skin without the removal delivery technologies range from the development of customer-specific of a significant amount of stratum corneum cells. This allows for solutions to out-licensing strategies. For more information, contact unique properties, including the ability to reapply patches while Degussa Corporation, Rohm America LLC at (877) 764-6872 reducing skin damage and irritation. For more information, (Option 4) or visit www.pharma-polymers.com visit Aveva Drug Delivery Systems at www.avevadds.com
FAST-DISSOLVE TECHNOLOGY PEG DERIVATIVES
Cardinal Health’s Zydis® fast-dissolve technology can help enhance a NOF Corporation has developed excellent quality activated PEG derivatives ol 6 No 2 ol 6 No product's performance in several ways. The rapid dispersion and coating (SUNBRIGHT Series), which are ideal for preparing pharmaceuticals and V with the Zydis technology in the buccal cavity creates products that can biomedical products. NOF not only manufactures various molecular decrease onset time, modify absorption, increase bioavailability, and weights of Methoxy-PEG with low polymer distribution, but also produces augment therapeutic efficacy. Because the Zydis technology dissolves high-purity Methoxy-PEG-OH in which diol contents as impurities are ebruary 2006 instantly on the tongue in less than 3 seconds, it can be swallowed claimed to be lower than any other supplier’s PEGs in the world. The F without water. For more information, contact Cardinal Health at SUNBRIGHT Series includes polyalkylene glycols with various functional (866) 720-3148; [email protected]; or visit www.cardinal.com/zydis groups, which make them the most appropriate material to produce PEGylated drugs, PEGylated-Liposomes, and polymer micelles. For more information, contact NOF Corporation at (914) 681-9790 or visit www.nof.co.jp/dds Drug Delivery Technology Drug Delivery Technology
63 MICROACTUATOR TECHNOLOGY CELL ABLATION TECHNOLOGY
Osmotex has developed a unique electrokinetic micropump TransPharma Medical has applied well-proven RF Technology commonly (or generally, a microactuator technology), which is extremely small used in minimally invasive surgery, such as laparoscopic procedures, to - thousands of individually addressable actuators can be integrated create RF MicroChannels in the skin surface. Each of these RF on a microchip. The microactuator contains no moving parts, can MicroChannels is of precise dimension to enable reproducible delivery of be produced cheaply by standard microfabrication, and runs molecules via a specially formulated patch. RF-MicroChannel drug delivery typically on 1 to 20 Volts (compared to 100s to several 1000s of is ideally suited for drugs that must be injected, as well as for a variety of Volts for competing technologies). It can pump, mix, or valve a orally delivered drugs with poor bioavailability. These include polypeptides wide range of liquids without affecting their properties, and is stable and other large molecules, small molecules (including existing transdermal and reliable, having a long service time. Osmotex’s business is drugs), regional and topical applications, and enhanced immunization to license its actuators to producers of all kinds of microfluidics programs. TransPharma has adapted and modified the RF Cell Ablation end-user products. In connection with this, Osmotex will enter into Technology to enable the creation of precise RF-MicroChannels on the skin co-development with companies to incorporate its actuators into surface in a highly controllable manner. For more information, visit complete MF systems. For more information, visit www.osmotex.no www.transpharma-medical.com
CONTROLLED DRUG INFUSION SYSTEMS FOR DRUG ADMINISTRATION SmartDose® is a simple-to-use “plug & play” disposable drug delivery system, which efficiently addresses the growing needs for increased safety, improved ease of use, and cost containment in controlled drug infusion. It is a revolutionary disposable system composed of a self-powered, prefilled container with dedicated inlet & outlet ports for both closed Medimop Medical Projects Ltd., a West Pharmaceutical Services, Inc., ol 6 No 2 ol 6 No drug transfer and drug infusion, V company, is a leader in the world market for transfer, mixing, and respectively. As a pharmaceutical administration systems for injectable pharmaceuticals. The company partner, the added value is that designs, develops, and manufactures needleless devices and product SmartDose® improves the handling packaging systems that safely and efficiently connect, interface, mix, and safety and ease of use of your drug, ebruary 2006
F filter injectable drugs in vials, bags, ampoules, and syringes. Medimop combined with unmatched patient compliance, directly influencing your offers a variety of products to meet drug formulation and disease-specific drug's acceptance and its clinical efficiency. Within the pre-hospital, in- needs. Medimop’s products offer users safer and simpler product hospital, ambulatory, homecare, emergency, or military environment, the handling, reduced medication errors, and improved patient compliance. All infusion drug specifications are strictly respected - from reconstitution Medimop products are 510K approved by the United State Food and Drug through to infusion. For more information, visit Pro-Med Controlled Administration and carry CE certification. For more information, visit Infusion Systems at www.pro-med.net Medimop Medical Projects at www.westpharma.com Drug Delivery Technology Drug Delivery Technology
64 PHARMACEUTICALS, WILLIAMS, MBA diabetes.” therapy for such asinsulin other areas, applications in COPD alongwith asthma and prevalence of the increasing billion dueto ex could grow toin of that by theend many believe $10 billion,and currently nearly huge. Itis V such as technologies, delivery with pulmonary drug sy local and potential for “The market entaira’s, is MS. LESLIEJ.
stemic cess of $25 the decade President &CEO VENTAIRA INC. delivered viainhalation. created opportunitiesfor existingornovel drugsthatmaybemore easily inhaled drugsfor thetreatment ofasthmaandtakingadvantage of newly Inc., todiscusshow hercompany iscurrently developing itsown proprietary interviewed LeslieJ. Williams, President &CEOof Ventaira Pharmaceuticals, more andeffectively. efficiently DrugDelivery Technology recently the company candeliverrespiratory andsystemically activedrugstothelung soft mist. sizecharacteristicsofthe The particle neutralizes the droplets, resultinginanexpelled droplets. into uniform A subsequent electricfield tension andresultsinthebreak upofthefluid chargessurface thatovercome liquidsurface resulting intheinductionofrepelling surface, chargesaerosol. thefluid’sAn electricalfield ofasoftmist droplet leading totheformation isappliedtoaconductive liquid electrical field electronic nebulizationprocessinwhich an Electrohydrodynamics (EHD). This isan on auniqueliquidaerosoltechnology called A: device in? Whatstage isthe inhalation device. Pleasedescribe Ventaira’s Mystic Q: proprietary Mystic Into Medicine Science &Technology Breathing V V V entaira Pharmaceuticals: V entaira’s Mysticinhalationdevices arebased novel pulmonarydrugproducts intheoutpatientsetting. With its improving current patienttherapies andqualityoflife byproviding entaira isaspecialtypharmaceuticalcompany dedicatedto TM inhalation technology (Electrohydrodynamic orEHD), and backofthe throat.Ourdevice can beused inthemouth There isminimal adherenceofdrug deepbreaths. have timetakingshort adifficult function who those withcompromisedrespiratory makes easyforchildren,olderpatients,and it very the device todeliver theappropriatedose. This device andbreathes normally. The breathtriggers onthe is readytotake hismedication,heturns b to andthroughthelungs. enabling consistentdeliveryefficiencies, ofdrug high withvery uniformly sizedparticles fundamental attributesofproducingsoftclouds Insummary,properties. thetechnology hasthe together withtheflow rateandelectricalfield and chemicalcharacteristicsoftheformulation, aerosol canbecontrolledby adjustingthephysical ut importantly, areeasytouse. When thepatient Our hand-helddevices arenotonly efficient, 65 Drug Delivery Technology February 2006 Vol 6 No 2 66 Drug Delivery Technology February 2006 Vol 6 No 2 A: Inhalers (MDIs)? (DPIs) orMetered Dose from DryPowder Inhalers V Whatdifferentiates Q: halfof2007. units thefirst commercialproduction 2006 andfinal halfof commercial device thefirst functional prototypesofthe production units. We expect tohave w w 2006. We arealsoaggressively clinical trialinthesecondhalfof use thesedevices inourPhaseIIb oftests. complete battery We planto anda production-molded parts fully devices integrated withfull 2006. This meansthesedevices are V of ourdevice, we willhave Device reproducibility. have shown excellent dose-to-dose with different andwe typesofdrugs, required ofpatients. the device effort ortheinspiratory inusing This canbedue todifficulty dosingvariability.have significant much lower and delivery efficiency for decades. These devices have a and MDIs. inhalation technologies, suchasDPIs improvements over othertypesof the device tobeeasyuse. These are Along withthesefeatures,we expect minimal dose-to-dosevariability. size,we particle haveuniform shown Because ofthesoftmistattributesand delivery.topical lungorsystemicdrug regional lungdelivery, enabling both technology enables ustotarget thisunique our formulations, addition, by sizewith varying particle togetthesameeffect.drug In tothelung,thusrequiringless drugs technology deliver canmoreefficiently erification Testerification (DVT) unitsinQ1 entaira’s Mystictechnology orking onourcommercialdevice, hich isasmallerversion ofour We As forthestageofdevelopment MDIs andDPIshave beenaround
have proven thatourMystic that by theend ofthedecade could nearly $10billion,andmany believe V delivery withtechnologies, suchas drug and systemicpulmonary program called Acuair A: technology? potential for Ventaira’s Whatisthemarket Q: A: and what Phaseare you in? are you currently working on, Whatclinicalprograms Q: easy-to-use device. the active delivered drug withour treatment ofasthma.Fluticasoneis forthe formulation proprietary and commercialization. product forPhaseIIIdevelopment trial inasthmaticsandlicensethe We of2006. quarter this studyinthefirst technology. Ourplanistocomplete the clinicalapplicationofour We conducting ascintigraphy/PK study. trial with Acuair andarecurrently we workingpartner intheasthmaspace. look tolicensethisprogram toa initial GSKpatentsexpire. We will our technology by 2010when the fluticasone/salmeterol forusewith goal istohave ourcombinationof have peaksalesof$8billion.Our marketed drug Advair®, which may GlaxoSmithKline’s currently similarto combination isvery for thetreatmentofasthma. This a fluticasone/salmeterolcombination chemical classesandtherapeuticareas. These compoundsspanavariety of administered withthistechnology. ofcompounds thatcanbe portfolio entaira’s, ishuge.It is currently
have completedaPhaseIclinical e then plantoinitiateaPhaseIIb The market potentialforlocal We We We As forwhat stagewe arein— xpect thestudytodemonstrate
are alsoexpanding our are currently workingare currently ona are also currently workingare alsocurrently on ® , which isour • •D used totreatavariety ofdiseases. wide variety ofsmalltolarge molecules Our technology canpotentially deliver a andeffectivelyefficiently viainhalation. allow ustotarget regional lungdelivery we is easyforpatientstouse. Additionally, tothelungand atgettingdrugs efficient market. Mystictechnology ismore availablecurrently devices onthe technology isanimprovement over insulin therapy fordiabetes. applications inotherareas,suchas asthma andCOPDalongwith to theincreasingprevalence of gr •D We products forinhalation. pharmaceutical technologyformulation todevelop new utilizing ourMysticinhalationand businessbyspecialty pharmaceutical Phase IandIIdevelopment. andoptimization identification in thevalue chainby focusingonlead We company. pharmaceutical integrated not have planstobecomeafully trials andcommercialization. We do forPhaseIII Phase IIbandthenpartner product fortreatingasthmathrough A: Business strategy? commercialization strategy? Whatis Ventaira’s Q: ow
have capabilitiesthat formulation are buildingvalue by: believe we areoptimally positioned (NCEs). for theirnew chemicalentities inhalation asamode ofdelivery their own andusing drugs; generics; lifecycle managementof interested inlicensing“super” companies pharmaceutical Strategically with partnering utilizing Mystictechnology; and inhalation device; As Imentionedpreviously, our Our businessstrategy isto builda We
to inexcess of$25billiondue ev ev
plan todevelop our Acuair eloping proprietary products eloping proprietary eloping abest-in-class Our Mystic inhalation and Q: The FDA has strict device available by the first half of formulation technology are supported guidelines in place for 2006 as well as completion of a by a comprehensive portfolio of patents delivering drugs via inhalation. scintigraphy/PK study by the second and technical know-how. Please describe these quarter of 2006. Then, if all goes well, restrictions and how Ventaira’s we will initiate our Phase IIb efficacy device meets these guidelines? study for the treatment of asthma. Our Q: The pulmonary drug commercial device will be available by the first half of 2007, and we plan to delivery field has seen A: It has been difficult to get new have our fluticasone/salmeterol significant advances in the inhalation drug products approved. formulation for treating asthmatics past 5 years, where do you Usually this difficulty is due to ready for clinical trials. We are also see this field going? performance limitations of the device advancing our overall formulation component and not clinical space as well, and our goal is to A: I believe there is tremendous limitations related to the drug design two additional base growth opportunity in the pulmonary substance. For example, the device formulations to the EHD spray space. drug delivery space. The prevalence of may not be able to consistently pass asthma and COPD continues to grow the FDA’s expectations for Dose along with the demand for improved Content Uniformity, meaning the Q: In your opinion, same dose is delivered each time the treatments. Of growing interest is using what are the biggest challenges the huge surface of the lung as a portal inhaler is used. I don’t foresee any you and for systemic drug delivery. Systemic changes in the regulatory applications hold enormous potential. It environment or expectations related your company face? is a very exciting time for those of us to this. The FDA will continue to I think the biggest challenge we working in this field because the drug expect the device to perform reliably A: face is reducing the device technology Exubera, inhaled insulin, developed in over a range of anticipated into practice. By this I mean partnership between Nektar and Pfizer environmental conditions. I expect demonstration that the device can be is expected to be approved in the US the FDA’s device performance built at the right size with the intended late 2006. This is a major breakthrough expectations will be consistently components and that it works properly for using pulmonary inhalation for applied across different review through the intended dosing regimen treating systemic disease. The critical divisions as more applications are and shelf life. It is easy to get carried factor determining the success of filed for non-respiratory clinical away with prototypes that look systemic pulmonary drug delivery is the objectives, such as insulin. We have promising but are not a practical ability to reach the deep lung. The demonstrated that Ventaira’s Mystic execution of the intended design. challenge is to produce a fine mist or technology meets these requirements. However, we are already on our way powder comprising uniform particles of achieving this. By the middle of 2006, small diameter, 2 to 5 micrometers, and we will have our final production to deliver it as a well dispersed cloud at Q: What are the next steps ol 6 No 2 ol 6 No
design complete. We have an V the right speed to reach the alveoli. for the company and its experienced team that is committed to Some estimate that if an inhaler can technology? assuring that we have an effective, prove that it can deliver drug deep into efficient, and easy-to-use device. ♦ the lung and deliver systemic drugs, the A: We have a busy 2006 planned. ebruary 2006 market for such an inhaler could reach First and foremost, we will remain F in excess of $25 billion a year. The field focused on bringing our device to is growing rapidly, and it will continue completion – demonstrating as we get further experience. Pulmonary manufacturability and inhalation of drugs, such as insulin, is commercializability. We also plan to likely to be a welcome advance for demonstrate the application of the patients whose only alternative at this technology in patients with our lead Drug Delivery Technology time are injections. compound. We plan to have our DVT 67 QUICK-DISSOLVE F I L M S
Quick-Dissolve Strips: From Concept to Commercialization By: Caroline M. Corniello
INTRODUCTION
Watson Inc. has been manufacturing water-soluble delivery system called Quick-Dissolve Strips. Quick- films for more than 40 years. Mr. John Watson, a Dissolve Strips are a convenient way to deliver active water-soluble film pioneer, envisioned supplying his pharmaceutical ingredients (APIs) to the consumer added value ingredients to his bakery customers in a because they are easier to swallow, as the filmstrip novel delivery system called Sol-U-PaksTM. Sol-U-Paks dissolves in the oral cavity before ingestion. No were designed from a cold water-soluble polymer, water is needed for the filmstrips to dissolve, so hydroxypropylmethylcellulose (HPMC), and were this is an added convenience for the consumer. intended to be used as a unit-dose delivery system. Water would be needed if the API were to be delivered This ensured that the consumer would be able to using the traditional tablet/capsule delivery system. consistently add the ingredient to a batch with Quick-Dissolve Strips are also an improvement over accuracy, and the batching operator would not be elixirs, which are messy and difficult to dispense exposed to the added value ingredients. Using a with accuracy. vertical form, fill, and seal machine, the cold water- The primary focus of this article is to review soluble Sol-U-Paks would be filled at Watson Inc. some of the physical attributes needed to design a with the customer’s ingredient. Next, the company Quick-Dissolve Strip to ensure consumer acceptance. would ship the package to the customer, and the A secondary discussion will focus on a different batching operator could then immediately add the water-soluble film, which is intended to deliver the Sol-U-Pak to the batch. API vaginally. Finally, taste-masking and mouth-feel In the past 5 years or so, the US consumer has techniques used to design caffeine and benzocaine come to accept these water-soluble films as a novel Quick-Dissolve Strips will be discussed.
FILM CHARACTERISTICS Dissolve Strip designed using polyethylene from the following polymers: pullulan, & PROPERTIES oxide (PEO) as its polymer would be a starch, HPMC, HPC, sodium alginate, poor choice due to the lubricous nature pectin, and CMC. By carefully balancing Normally, most consumers are of this polymer. The lubricous nature the mechanical properties, solubility rate, expecting to see a consistent looking causes the filmstrip to become gummy taste, and mouth-feel (texture) for the in the mouth, which in turn causes an filmstrip, these polymers can be employed ol 6 No 2 ol 6 No Quick-Dissolve Strip that is stiff, flat, and V doesn’t curl on the edges. For consumer unfavorable mouth-feel for most formulas. to design Quick-Dissolve Strips. acceptance, the water-soluble filmstrip must However, most of the other film Due to the inverse proportional be robust enough to be removed from the characteristics can probably be obtained. relationship between mechanical properties unit-dose packaging without breaking. The On a favorable note, PEO is an excellent and solubility rate, these two properties ebruary 2006 F strip must also dissolve readily in order to choice when considering an application must be carefully balanced when designing deliver the API rapidly when placed on the like a whitening strip. This is due to the a Quick-Dissolve Strip so that the stiff tongue, so that a gummy texture is avoided. mucoadhesive nature of PEO, which will filmstrip can be efficiently cut to size, and The most important component in the film enable the polymer to stick to the gum line filled into unit- dose packaging while still matrix, which can achieve these for an extended period of time. having rapid dissolution. By controlling the characteristics, is to choose the correct In stores today, consumers can find molecular weight distribution (MWD) of Quick-Dissolve Strips that have been made the film matrix, these two properties can be
Drug Delivery Technology Drug Delivery Technology polymer system. For example, a Quick-
68 QUICK-DISSOLVE F I L M S
Because most Quick-Dissolve Strips are limited to a specific width (0.875 in) and Table 1. General Trends of MWD Affects length (1.25 in) due to the size of the oral on Physical Properties of Filmstrips cavity, we will discuss changing only the thickness in this article. If desired by the customer, Watson can vary the other two Physical Property Low MWD Polymer High MWD Polymer dimensions, depending on the application. By increasing film thickness, the weight Viscosity of Solution Low High per strip will increase; therefore, the load of the API will increase proportionally for the same film matrix. Table 2 provides examples Solubility Rate of Filmstrip Rapid Slow on how increasing film thicknesses can deliver a higher load of API per filmstrip. To date, there are Quick-Dissolve Strips on the market Stress – Strain Behavior Brittle Filmstrip Flexible Filmstrip that weigh up to 100 mg (due to an increase in filmstrip thickness) and can thus deliver up to 25 mg of API per filmstrip. A negative impact optimized. Table 1 shows some general trends Another characteristic of the vaginal delivery of increasing the film thickness is that the of how the MWD of a polymer will affect film is that after dissolving, the film must go solubility rate increases. If one of the other various physical properties of filmstrips. undetected by the consumer. Low viscosity, dimensions were increased instead, the impact Usually, when designing Quick-Dissolve 88% hydrolyzed polyvinyl alcohol (PVA), is an on solubility is not as great; however, the Strips, a polymer with a low MWD or acceptable polymer for this application because filmstrip may not fit comfortably in the viscosity, such as HPMC E5 or pullulan PI-20, this polymer exhibits a balance of flexible and consumer’s mouth. For some applications, it is employed. When the desired physical tough stress-strain behavior with rapid may be acceptable to deliver higher loads of properties aren’t obtainable using a single low solubility at 37ºC. Polyvinyl alcohol is an API by instructing the consumer to take viscosity polymer, mixing various viscosity interesting polymer because of its ability to multiple strips per day. grades of the polymer may overcome this hydrogen bond. The hydrogen bonding of the For consumer acceptance, there is a problem. When mixing a high viscosity 88% hydrolyzed PVA material allows for limited amount in which the solubility rate can polymer with a low viscosity polymer, the excellent mechanical properties when be increased because the slower dissolution Quick-Dissolve Strip will generally have compared to other polymers at the same rate will usually cause the filmstrip to feel mechanical properties similar to the higher viscosity that aren’t capable of hydrogen gummy in the oral cavity. If the filmstrip needs MW polymer, and the solubility rate will be bonding. In recent years, this polymer has been to dissolve slowly over a prolonged period of similar to the lower MW polymer. When approved by the FDA as a GRAS ingredient time, then the film matrix needs to be designed optimizing these properties, two of the same with limited-use levels in the supplement in such a manner that a gummy mouth feel is polymers can be employed or they can differ. arena; therefore, there probably will be avoided. Watson Inc. has designed some innovative Quick-Dissolve Strips designed filmstrip systems in which a gummy mouth
VAGINAL FILMS using this polymer in the future. feel is avoided when the dissolution rate is 2 ol 6 No increased for a prolonged period of time, so V For a project where the API is going to be CHALLENGES that the product is acceptable to most delivered to the vaginal area, a very different consumers. Additional work needs to be water-soluble film matrix is desired. A It is challenging to incorporate completed before it’s determined whether the ebruary 2006 common characteristic of this film will be the pharmaceutical actives into Quick-Dissolve API is also delivered over a prolonged period F need to dissolve rapidly in the vagina; however, Strips for several reasons. First, there is limited of time in the oral cavity. the mechanical properties will be quite space available in the film. Currently at Caffeine different for the vaginal delivery film. This Watson, the maximum amount of API that can film needs to be flexible and tough enough so be incorporated is approximately 30% of the Designing Quick-Dissolve Strips is also that when folded into quarters, the film can be film matrix’s composition. Therefore, this challenging because the bitter taste of the API
inserted into the vagina without breaking. delivery system is not suitable for all APIs. must be overcome. In our development efforts, Drug Delivery Technology
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Table 2. Effect of Film Thickness on Amount of Active Delivered Per Filmstrip
Filmstrip Thickness (mil) Weight of Filmstrip (mg) Amount of Active Per Filmstrip (mg)
2.0 52 15.6
2.2 58 17.4
4.0 104 31.2
5.0 130 39
we were able to design Caffeine Quick-Dissolve Watson Inc. has explored encapsulating need to further optimize the manufacturing Strips that contain 16 mg of caffeine per each the active API as a means to minimize the process to limit the degradation of the API and 58-mg filmstrip. For this project, overcoming detection of bitter flavor and has determined to ensure the integrity of the encapsulation. the bitter taste of caffeine was difficult because that several factors must be considered to do More than likely, further testing will need to be the filmstrip contained approximately 30% so. Encapsulating the active will expose the conducted on the Quick-Dissolve Strip to caffeine. In order to obtain a pleasant-tasting API to two manufacturing processes that can ensure that the active is released from the product, a variety of taste-masking aids were have a negative impact on stability; therefore, encapsulation material into the digestive track employed. Primarily, the flavor chosen must extensive testing will need to be conducted to at the correct time, and that the API is complement the bitter off-notes of the active; ensure product integrity. Another consideration biologically available in the same manner as therefore, a flavor with menthol is the most is that the material used to form the currently approved by the FDA; otherwise, promising selection to be matched with caffeine encapsulation must also be stable through the clinical trials will need to be conducted. because menthol distracts from the organoleptic film manufacturing process, which is typically effects of the bitter taste. Secondly, with the a high moisture environment with elevated Benzocaine right balance of sweeteners, the perception of temperatures. The bitter notes will be detected For a Quick-Dissolve Strip that contains bitterness can be minimized. For this project, a in the filmstrip if the encapsulation doesn’t benzocaine, the challenge to balance the flavor sweetener that is detected late in the flavor hold up to the film manufacturing process. is quite different. In this case, the benzocaine profile is preferred, because the lingering Furthermore, because there is a limited amount numbs the taste receptors so quickly that in ol 6 No 2 ol 6 No V sweetness masks the bitter notes. Thirdly, bitter- of available space for this delivery system, certain formulas, the flavor can go undetected, blocking aids can also be employed. For this diluting the matrix with the encapsulation and the consumer only feels numbness. One particular active, all three techniques were material can further limit the amount of API in way to overcome this problem is to use employed to meet the objective of designing a the Quick-Dissolve Strip. sweeteners that release quickly in the flavor ebruary 2006 F pleasant-tasting Caffeine Quick-Dissolve Strip. When the customer considers these profile so that the flavor is developed before In an independent study, Dr. Roger E. Stier from factors and determines that optimizing flavor the consumer detects the numbing effect. Noville Inc. reports using similar techniques requires the API to be encapsulated, Watson Another way to obtain the desired balance of when masking the bitter notes of caffeine Inc. will need to carefully choose the flavor is to design a filmstrip that releases the and Lipitor.1 encapsulation material. The company will also flavor quickly, while following with a slow Drug Delivery Technology Drug Delivery Technology
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release of the benzocaine. For example, a REFERENCES BIOGRAPHY Quick-Dissolve Strip can be designed by sprinkling an encapsulated flavor onto the 1. Stier, RE. Masking bitter taste of surface of the film matrix before drying the pharmaceutical actives. Drug Delivery Technology. 2004;4(2):52-57. filmstrip. By doing this, the fast- dissolving encapsulated material will release the flavor before the slower dissolving filmstrip can release the benzocaine.
SUMMARY
In this article, Watson has discussed some of the key physical attributes needed to Ms. Caroline M. Corniello effectively design a Quick-Dissolve Strip so that there’s a balance of mechanical properties, is the Director of Product solubility rate, flavor profile, and mouth feel, Development in the Film which must be achieved in order to ensure Technology Division of Watson Inc. consumer acceptance. As a first step, the She earned her BS in Chemistry materials and lab equipment needed to design from Southern Connecticut State each project are carefully chosen once the University and her MS in Polymer application is well defined by the customer. By Science from the University of outlining the project goals and understanding Connecticut. Ms. Corniello joined the unique customer requirements, each goal Watson in December 2002 with can be met in a timely and cost-effective several years experience in manner. Furthermore, as various formulas are developing and manufacturing investigated, the data is collected and skillfully water-soluble films in a commercial interpreted to choose effective direction and environment. At Watson, she is targeted product specifications. When the customer approves a formula and the target currently researching and product specifications, a pilot run is performed developing the applications of so that additional equipment needed is pharmaceutical-grade films in identified and purchased to optimize the cosmetics and drug delivery. manufacturing process. Next, a protocol is written so validation work can be executed in ol 6 No 2 ol 6 No accordance with the customer’s specified V needs, and finally, a report is written so that the formula can be commercialized. ebruary 2006 F Drug Delivery Technology Drug Delivery Technology
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Micellar Nanoparticles: A New Drug Delivery Platform By: Rahul Singhvi, ScD, President & Chief Executive Officer, Novavax, Inc.
INTRODUCTION Transdermal delivery involves application of a offers controlled disposition of the drug into the pharmacologically active compound onto the skin to patient leading to a steady blood-level profile, and achieve therapeutic blood levels in order to treat offers reduced systemic side effects and improved diseases remote from the site of application. Ever efficacy over conventional dosage forms in certain since the approval of Transderm-Scop®, the first cases. Transdermal delivery is particularly transdermal drug delivery system (TDDS) in 1981, advantageous for those drugs having significant there has been explosive research in the field of hepatic first-pass metabolism or degradation in the transdermal therapeutics for treatment of a variety of GI tract. Throughout the years, the US FDA has clinical conditions. Unmatched clinical benefits, approved more than 40 transdermal products, profound industry interest, existence of strong and spanning about 15 molecules, which amounts to niche markets, and regulatory precedence show why nearly $2.5 billion. TDDS has become a flourishing and viable dosage Micellar nanoparticles (MNP) is a form. The current transdermal therapeutics market is nanotechnology-based formulation that has achieved segmented into traditional formulations like gels, a breakthrough in transdermal therapeutics. It advanced delivery systems, such as patches, and represents a robust and versatile delivery system that novel physical technologies like microporation, can accommodate a range of therapeutic compounds iontophoresis, and sonophoresis. Transdermal delivery having varying physico-chemical properties.
MICELLAR patients. MNP drug delivery offers a ADVANTAGES OF AN NANOPARTICLES: potentially fast and inexpensive MNP-BASED PRODUCT A PRIMER pharmaceutical development model by using drugs already proven safe and Though currently available Micellar nanoparticle (MNP)-based effective to create new proprietary commercial topical dosage forms like ol 6 No 2 ol 6 No V emulsions (lotions) are attractive formulations. gels and patches successfully drive the alternatives for systemic drug delivery via The active ingredient is distributed drug into the systemic circulation, they topical application. The technology within the formulation in different present some drawbacks. The gels need to allows high concentrations of drug to physical forms micro/nanocrystals (or be applied over a large area of skin, and ebruary 2006 F penetrate the skin and functionally create particles), solution form in hydro- the composition may lead to skin dryness a drug depot in the stratum corneum and alcoholic/oil droplets, and micellar- in certain cases. The patches have very epidermis. This route of delivery provides associated form (Figures 1a and 1b). limited surface area for drug transport similar advantages of patch technology in MNP represents a multi-phase dosage leading to accumulation of drug in high avoiding both contact with the GI tract design with the active ingredient in concentrations beneath the applied area, and hepatic first-pass effects, and it is readily available solution form as well as which can result in significant skin cosmetically more acceptable to many in long-acting particulate depot form. irritation. Additionally, many people are Drug Delivery Technology Drug Delivery Technology
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FIGURE 1A FIGURE 1B Freeze-Fracture Microscopic Image of Estrasorb Showing Transmission Electron Microscopic Image of an MNP Emulsion Droplet Embedded in Micellar Matrix Preparation Showing Nano-Structured Emulsion
allergic to the adhesives used in patches. Table 1. Salient Features of MNPs They are also most expensive among the marketed transdermal products. MNP is the flagship delivery system h Topical dosage form for systemic delivery of pharmaceuticals developed at Novavax that is evolving as an innovative transdermal dosage form that h A unique nano-structured vehicle composed of nano-sized particles/droplets dispersed in a liquid crystalline matrix negates the drawbacks presented by gels and patches. h High drug loading capacity MNP technology has been applied for h The formulation utilizes excipients generally regarded as safe (GRAS) for humans estrogen replacement therapy with 17ß- by the FDA estradiol in Estrasorb®, the company’s first
h internally developed FDA-approved product 2 ol 6 No
The composition promotes quick penetration of drug into the skin without causing V irritation/tissue damage (Figure 2). Estrasorb is a nano-engineered topical dosage form that is approved by the h Utilizes proprietary high shear mixing process for manufacturing, offering improved product stability FDA for hormone replacement therapy. Estrasorb has been a revolutionary product in ebruary 2006
h Robust and versatile delivery system for a range of therapeutic compounds F nanotechnology-based pharmaceutical h Excellent bioavailability for many drugs showing significant hepatic first-pass product development that redefines h MNP technology – best suited for lipophillic small molecules transdermal therapeutics. Estrasorb validates MNP technology and is the only emulsion- h The intellectual property behind the MNP technology is protected by worldwide based formulation in the topical estrogen patents replacement market. Drug Delivery Technology Drug Delivery Technology
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FIGURE 2 FIGURE 3 Estrasorb® - First Commercially Product Development Pipeline at Novavax Based on MNP Technology Available Product Based on MNP Technology
PRODUCT PIPELINE BASED ON MNP TECHNOLOGY
Novavax has multiple projects in its drug delivery pipeline, which are focused on projects that are compatible with MNP technology and target large, unsatisfied markets (Figure 3). Currently, the company’s focus is on topical delivery, but it believes its technologies may have broader applications. Several small molecular weight compounds have been evaluated to prove the versatility and expandability of the MNP •A longer duration of action (drug • There is a possibility of administration ol 6 No 2 ol 6 No V technology. Preliminary studies (Figures 4a depot) exists, ranging from of drug combinations for improved through 4e) highlight the following findings: approximately 18 to 36 hours after therapeutics (unpublished results). single topical application, sustained- •Technology extends to non-hormonal, ebruary 2006 release formulation; F small molecular weight compounds; • Maintenance of steady plasma drug • There is a rapid onset of action (see levels is achievable on multiple dosing fentanyl graph), the formulation can be (unpublished results) within therapeutic easily optimized to tune this phase; window; and Drug Delivery Technology Drug Delivery Technology
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FIGURE 4A FIGURE 4B BIOGRAPHY
FIGURE 4C FIGURE 4D Dr. Rahul Singhvi was appointed President and CEO of Novavax in August 2005. He joined the Company in 2004 as Vice President, Pharmaceutical Development and Manufacturing Operations and was appointed Senior Vice President and Chief Operating Officer in April 2005. He is charged with restructuring the company to focus on its core competency of new product development and innovation and drive shareholder value. Prior to joining Novavax, Dr. Singhvi spent 10 years with SUMMARY & OUTLOOK Merck & Co, most recently serving as FIGURE 4E Director of Vaccine and Sterile Operations Transdermal drug delivery is not suited in the Merck Manufacturing Division. In nor clinically justified for all drugs, yet it is this position, Dr. Singhvi was responsible viewed to be much more limited than it for operating a manufacturing unit actually deserves. MNP technology helps to producing a new biological product and incorporate and deliver many therapeutic initiating the start up of a second biological product manufacturing unit. In compounds that are otherwise viewed as addition to his functional expertise unsuitable for transdermal delivery. The within process development and MNP technology allows fast, low-cost manufacturing, Dr. Singhvi was a product development compared with typical recognized leader within Merck & Co., development of new chemical entities. From Inc. for the depth and breadth of his ol 6 No 2 ol 6 No proof-of-principle in a validated preclinical expertise, and led several cross-functional V Plasma Distribution Profile of model through advancing into a Phase I study teams responsible for technology transfer Investigational Compounds in humans requires approximately 12 months and development of new products. Dr. Formulation in MNP to complete. The data from Novavax’s Singhvi holds several patents in the area
of cell culturing systems and has co- ebruary 2006 preclinical studies show high probability of F authored numerous publications, book clinical success within a shorter development chapters, and abstracts on biochemical time horizon and a lower cost than a typical engineering and cell physiology. He NDA. The results expand the product earned both an MSc DSc in Chemical opportunities for Novavax into attractive Engineering from MIT, Cambridge, an MBA therapeutic categories, such as pain, urology, from The Wharton School, Philadelphia, and allergy. Novavax filed two INDs with the and a Bachelor of Technology from IIT FDA at the end of 2005 for two non-hormone (Kanpur), India. Drug Delivery Technology product candidates. 75 QUALITY C O N T R O L
Designing Quality Into the Manufacture of Adhesives Targeted for Healthcare Applications By: Katherine L. Ulman, Irena Ziec, and David J. Neun, PhD
ABSTRACT
With additional regulatory and quality Corning and Rohm and Haas medical adhesives requirements for active and inactive pharmaceutical alliance has defined and implemented principles ingredients, it is increasingly important for of “quality by design” into manufacturing and suppliers to keep abreast of regulatory trends while distribution operations for producing pressure- partnering with pharmaceutical manufacturers to sensitive adhesives targeted for transdermal drug understand and meet their product needs. The Dow delivery systems and drug-loaded patches.
INTRODUCTION ESTABLISHING principles. Criteria defined as critical by A ROBUST the team include a quality management Emerging regulatory trends for QUALITY SYSTEM system, management commitment to pharmaceutical products continue to focus quality, quality training program(s), on topics such as global harmonization, Although the ISO 9000 family of complete product traceability (throughout process analytical technology (PAT), good quality management standards has earned the entire supply chain), manufacturing practices (GMPs), quality by a worldwide reputation as a “generic process/product/document control, design, science-based regulations, and risk- management system” that delivers a contamination control, and change based pharmaceutical assessments. These valuable framework for quality, the control aligned with customer initiatives challenge healthcare standards focus mainly on the “what” notification of change. manufacturers to build quality and safety rather than the “how” and on the end into their products from initial development result rather than the entire RISK-BASED APPROACH TO and design, through manufacture, launch, manufacturing process. In today’s CRITICAL GMP ACTIVITIES and post-launch surveillance. As a result, environment, it is also essential to pharmaceutical manufacturers continue to incorporate appropriate GMP principles Governmental regulations (laws, place higher expectations for improved raw into the production, handling, and standards, and guidelines) are developed material quality and safety on their distribution of pharmaceutical products. to ensure the continued production of suppliers by asking them to help define and However, selecting the appropriate products that are safe and effective for ol 6 No 2 ol 6 No build the proper level of controls into their V guidelines and level of GMPs to their intended use. In the US, these manufacturing and distribution operations. implement can pose a challenge for regulations include compliance to 21 Incorporating quality into the design CFR 210/211 for companies producing of a product not only involves building in developers, raw material suppliers, and finished product manufacturers.1-3 bulk pharmaceutical active ingredients
ebruary 2006 critical quality elements of GMPs (eg, F and finished drug products. In addition, a traceability, change control, and notification To ensure the establishment of GMP guidance specific to active of change and contamination control) and proper manufacturing controls for pharmaceutical ingredients (ICH Q7A) monitoring quality indicators from pressure-sensitive adhesives targeted for has been drafted and accepted or adopted development throughout a product’s life use in drug delivery systems, the Dow as law by many countries. In the US, ICH cycle, but also includes implementing Corning and Rohm and Haas team agreed Q7A is currently accepted as a guidance elements of continuous improvement and to manufacture the adhesives in facilities document; however, inspectors often refer Drug Delivery Technology Drug Delivery Technology risk management principles. capable of implementing critical GMP
76 QUALITY C O N T R O L
to it when conducting GMP inspections of minimize contamination, improve people who handled it, equipment used to both bulk and finished pharmaceutical product process control, and make informed manufacture and/or test it, packaging operations. decisions about inconsistencies or components (eg, containers, labels, etc) Today, regulations do not specify quality abnormalities that could occur during the used to package it, and the handling and and safety operations for excipients; however, manufacturing process. Operators should storage conditions used to warehouse and guidance documents (from IPEC, PQG, also be trained in proper handling and ship it. To ensure good traceability, WHO) identify critical GMP elements to labeling of the finished product. containers should be clearly labeled to consider. Additionally, excipient suppliers identify the contents. Materials not required should understand the risk of what could go • Shipping/Receiving/Warehousing: for operations should be removed from the wrong, and if it went wrong, what impact it Shipping, receiving, and warehousing production area, including removal and could have on product safety and efficacy. personnel are responsible for receiving, destruction of excess labels. Effective use of risk management can handling, storing, and transporting raw These measures help ensure full facilitate better, more informed decisions and materials, intermediates, and finished traceability of product, manufacturing, provide regulators with greater assurance of a products. Procedures must be in place testing, packaging, storage, and distribution company’s ability to deal with potential issues. to prevent mix-up and contamination of operations, which can simplify root cause material during each of these analysis of noncomplying product, help Quality Management System operations. identify other potentially impacted batches, & Management Commitment and help provide assurance for nonaffected To ensure product safety and efficacy, an • Quality Assurance/Control: The batches. excipient manufacturer should implement a quality department is responsible for quality management system that has the full managing and controlling quality Process/Product/Document Control support and commitment from the aspects of raw materials, intermediates, To meet emerging requirements, management team. The team’s role and and finished product. For instance, raw excipient manufacturers need to monitor, responsibilities should include periodic review material certificates of analysis (COAs) understand, and control their raw materials, of quality-related topics and issues, including and identity checks are made to ensure intermediates, and finished products complaints, audit findings, nonconforming the product is what it is supposed to be products, and supplier issues. throughout their entire supply chain (from and meets lot acceptance criteria. receipt of materials through delivery to Quality personnel review and approve Quality Training Program pharmaceutical manufacturing facilities). changes (eg, equipment, process, raw A program dedicated to ensuring proper materials, and test methods) prior to employee training, including quality system PROCESS CONTROL evaluation and implementation. They training in GMPs, is essential for everyone also review/approve batch records prior involved in producing, packaging, storing, and It is important to understand and to product release to ensure complete shipping pharmaceutical excipients. The plan for quality (ie, to control and manage and accurate records (eg, acceptable training program should define how changes variability) at the design phase versus critical process parameters and final lot in regulatory requirements are monitored, testing for compliance at the end. A good ol 6 No 2 ol 6 No
testing, required signatures, and V interpreted, and communicated to employees process design should include understanding required documentation). and should include the following: the impact on quality and performance when certain parameters are varied. By • Management: Properly trained Product Traceability Throughout striving for better process understanding ebruary 2006 management and staff are important to the Entire Supply Chain and capability analysis, excipient suppliers F demonstrate management’s commitment It is important to be able to trace the should be able to design quality in and for GMP operations and compliance. final product from raw material receipt facilitate risk-based decisions for through production of intermediates and continuous improvements. Validation • Operators: Proper operator training is finished products (eg, cleaning and change control should be considered paramount as properly trained operators agents/operations, equipment identification, to ensure process control.
can play a significant role in helping to and detailed batch records), including Drug Delivery Technology
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PRODUCT CONTROL review, approval, release). Each batch toxicity. When possible, a final rinse is production record should include process made with solvent used in the product. In addition to controlling the process, SOPs and pertinent product information, The complexity and thoroughness of the the product needs to be monitored and such as raw material/quantity, packaging cleaning process is determined based on controlled throughout its life cycle. Good material(s), labeling, label reconciliation, knowledge of other materials product control includes such factors as: equipment used, and operators. Batch manufactured in the same equipment records should be reviewed and approved by and can be simplified by campaigning • Contamination control to verify QA personnel prior to product release. similar products. adequacy of cross-contamination prevention, sanitary conditions, Contamination Control • Material Handling: When possible, ventilation, lighting, cleaning Although no specific guideline or bulk materials are used and direct agents/program, etc. regulation requires the identification and operator handling is minimized. control of impurities in excipients, this Personal protective equipment is • Nonconforming product control, factor should be considered as critical during used to minimize contaminations whereby a separate area is designated the manufacture of pharmaceutical when appropriate. and controlled for materials that do not excipients, and several API guidelines can be meet requirements. referenced (ICH Q3C), USP NF <467> , and Change Control Aligned With Customer Ph Eur. general chapter 5.4.5-7 Even Notification of Change • Corrective and preventive actions manufacturing an excipient in a closed In the early stages of product (reprocessing/rework disposition, system can lead to product contamination; development, a formulator selects adhesive rework authorization, therefore, contamination control should products that aid in delivering the drug corrective/preventative action plans, and include a review of building and facilities substance as desired. Once the formula and progress reviews). design, materials flow, and storage, cleaning process have been defined and optimized, agents and operations, lubricants, the impact of adhesive variability (batch-to- • Sample retention, in which twice the environmental monitoring/control, and pest batch) is determined, and final scale-up to amount of sample required to perform control, as well as manufacturing, testing, pilot and production equipment is all specification testing is kept for each packaging, and storage operations. completed. At this point, it is critical for batch for at least 1 year past the At GMP manufacturing sites, subsequent batches to be within established expiration date, re-evaluation date, or procedures are developed, documented, and specification limits and equivalent (quality after distribution is complete implemented to minimize potential sources and performance) to initial batch(es) (whichever is longer). of contamination, including: evaluated. Changes are inevitable; however, • Defined stability testing criteria and • Lubricants: Use of appropriate grade managing and controlling change is critical protocols. (eg, food grade). to ensuring consistent product quality and safety. Even changes that may seem minor ol 6 No 2 ol 6 No V • Out of specifications (OOS) procedure • Pest Control: Based on an (eg, raw material suppliers, change in consistent with FDA guidance.4 understanding of the process (eg, open cleaning agents, new test procedures or vs. closed system), appropriate equipment, or changes in manufacturing DOCUMENT CONTROL measures are taken to minimize location) should be properly evaluated for ebruary 2006 F potential contamination from insect, their impact on the final quality and Document control should include birds/bird droppings, rodents, and performance of the products being produced. control of all quality system documentation, similar contaminants. In addition, customers should be properly including the quality manual, procedures, notified of any change that could potentially and records (eg, master product files; batch • Cleaning Process: Cleaning agent impact the quality, safety, or performance of records; labels; and quality department selection includes a review for potential a product. Drug Delivery Technology Drug Delivery Technology
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ATTENTION TO EMERGING average timeframe for development and REFERENCES REGULATORY TRENDS regulatory approval of a new TDD system can be upward of 7 years for new drugs and 1. Rafidison P, Ulman K. Critical good As a result of global initiatives, about 5 years for generic drugs; however, manufacturing practice aspects to pharmaceutical manufacturing is currently there are steps that raw material suppliers consider for pharmaceutical excipients. transitioning from an art to a science, and can take to help facilitate and reduce these Business Briefing Pharmatech. excipient suppliers increasingly are being time lines:12,13 2003;118-123. asked to design quality into their products. 2. Good Manufacturing Practices: A Regulatory standards and policies are being • Provide adhesives (based on established Synopsis of Their Role and Rationale in designed to ensure continued quality, safety, adhesive technology) that can be easily Today’s Pharmaceutical Marketplace for and efficacy of pharmaceutical products, adjusted or customized to meet the Tubing. Dow Corning Publication, Form including excipients. In addition, the needs of various transdermal systems 52-1045-01. scientific framework being developed will (eg, adhesive properties, solubility 3. Lind J. Adhesives Research, Inc.: help support mitigation of risk while parameters, stability, and aesthetics). Focused product development process facilitating continuous improvement and results in successful custom pressure- innovation. Current trends include the • Form partnerships with pharmaceutical sensitive adhesive solutions for TDDS. following: manufacturers to support their needs Drug Delivery Technology. throughout the life cycle of their 2002:2(1):62-63. • US FDA cGMPs for the 21st century; products (eg, development, clinical 4. United States Food and Drug trials, scale-up and validation, launch, Administration Draft Guidance for • Controlling product source (eg, BSE); and continued supply). Industry: Investigating OOS test results for pharmaceutical production • Guidelines for residual solvents and/or • Ensure a healthy quality system staffed (September 1998), impurities in drug products: ICH Q3C, by necessary experts (engineers and www.fda.gov/cder/guidance/1212dft.pdf. laboratory personnel) and designed to USP NF <467>, Ph Eur. general chapter 5. International Conference on 5.4;5-7 effectively manage (identify, assess, Harmonization: ICH Q3C, Impurities: and internally and externally Guideline for Residual Solvents (July • ICH Guidance on Pharmaceutical communicate) change throughout the 1997), Development, ICH Q8, and draft life cycle of a product. www.ich.org/MediaServer.jser?@_ID=4 guidance on Quality Risk Management 23&@_MODE=GLB. 8,9 • Utilize toxicology studies, global Process, ICH Q9; and 6. In-Process Revision of USP28/NF23 regulatory resources, and Monograph <467>, Residual Solvents. • US FDA guidance on Non-clinical documentation [eg, drug master files Pharmacopeial Forum. 2005;31(5): Studies for the Safety Evaluation of (DMFs) or letters of access (LOAs)] to 1436-1447. Pharmaceutical Excipients.10 support product registration and
7. European Pharmacopoeia, 5th ed. Ph 2 ol 6 No
approval around the world. V Eur. general chapter 5.4. Limiting SUMMARY residual solvent levels in active • Produce adhesives in GMP facilities substances, excipients and medicinal using critical GMP principles of Based on emerging global trends, the products. ebruary 2006 process of controlling the quality and traceability, process/product F 8. International Conference on consistency of excipients while ensuring control, contamination control, Harmonization Draft Consensus they are well characterized, robust, and meet documentation/records, training, Guidelines: ICH Q8, Pharmaceutical and change control/communication regulatory requirements is a critical Development (November 2004), 11 of change. expectation for excipient suppliers. www.ich.org/MediaServer.jser?@_ID=1 Currently, the pharmaceutical industry’s 707&@_MODE=GLB. Drug Delivery Technology Drug Delivery Technology
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9. International Conference on BIOGRAPHIES Harmonization Draft Consensus Guideline: ICH Q9, Quality Risk Ms. Katherine Ulman is the Global Technology Coordinator Management Process (November 2005), www.ich.org/MediaServer.jser?@_ID=1 for Dow Corning Healthcare Industries and is the Technical 957&@_MODE=GLB. Coordinator at Dow Corning for the healthcare alliance between 10. United States Food and Drug Dow Corning and Rohm and Haas. Prior to this position, she Administration Guidance for Industry: was the Regulatory Manager for the Dow Corning Healthcare Non-clinical Studies for the Safety Industries. Ms. Ulman is a member of the American Chemical Society, American Evaluation of Pharmaceutical Excipients Association of Pharmaceutical Scientists, Control Release Society, and the IPEC of (May 2005), www.fda.gov/cder/guidance/5544fnl.pdf. the Americas. She has published and presented several papers in her field and 11. Lerke S. Pharmaceutical excipient has taught international courses on silicones for pharmaceutical/ biomedical sourcing challenges. Paper presented at applications and medical adhesives through Technomic Publishing Co. Ms. Ulman the AAPS Annual Meeting. Baltimore, earned her BSc in Chemistry from the South Dakota School of Mines and MD; 2004. Technology in 1976. 12. Ericsson T, Nairoukh T. A promising advance in transdermal reservoir patch technology. The Drug Delivery Companies Report. Ms. Irena Ziec is currently the Regulatory, EHS, and Process 2003;(Autumn/Winter):41-43. Engineer at Rohm and Haas Company for the healthcare 13. Best W. Transdermal components: six alliance between Dow Corning and Rohm and Haas. Ms. Ziec considerations for selecting a earner her BSc in Chemical Engineering from the University of transdermal drug delivery system component supplier. Drug Delivery Illinois at Urbana-Champaign in 2001 and is an active member Technology. 2004;4(5):58-61. of the Society of Women Engineers.
Dr. David J. Neun is the Global Regulatory Steward for Healthcare Industries of Dow Corning Corporation responsible for regulatory affairs and product stewardship. He is a Toxicologist with over 10 years experience with ingredients for ol 6 No 2 ol 6 No
V the healthcare market. Prior to joining Dow Corning Corporation, Dr. Neun was the Research Director for the Soap and Detergent Association in the United States, responsible for assessing alternative tests to
ebruary 2006 the use of animals and risk assessment for detergent products and their F ingredients. Drug Delivery Technology Drug Delivery Technology
80 COMPANY PAGE PHONE FAX WEB SITE
3M Drug Delivery Systems 3 800-643-8086 www.3m.com/dds
ALZA Corporation 2 www.alza.com assa International 4 203-312-0682 203-312-0722 www.assainternational.com
Baxter BioPharma Solutions 83 800-422-9837 www.baxterbiopharmasolutions.com
BD 29 800-225-3310 www.bdpharma.com
Cardinal Health 84 866-720-3148 www.cardinal.com/pts
Degussa 11 www.pharma-polymers.com
DPT 29 866-CALL-DPT www.dptlabs.com
Eurand 7 937-898-9669 www.eurand.com
Genzyme Pharmaceuticals 21 800-868-8208 www.genzymepharmaceuticals.com
INEOS Fluor 15 +44 (0) 1928 51 5525 www.ineosfluor.com
InnerCap Technologies 41 813-837-0796 www.innercap.com
INTERPHEX 17 www.interphex.com/delivery ol 6 No 2 ol 6 No V IOMED 5 801-975-1191 www.iomed.com
RDD X 2006 27 www.rddonline.com ebruary 2006 F
Scolr Pharma, Inc 9 425-373-0171 www.scolr.com
Valeo Partners 35 202-722-1864 www.valeopartners.com Drug Delivery Technology Drug Delivery Technology Watson 13 800-388-3481 203-932-8266 81 Understanding Competition By: John A. Bermingham
John A. few issues ago, our Executive Editorial Director, Dan Marino, asked me to write Bermingham a column on understanding competition. If you don’t mind Dan-O, I would like to joined Ampad as A put a little spin on that request.It was so bad that we named his alter ego Frank. President and CEO in A Fred was good. Frank was bad. August 2003 when It is always important not just to know what’s happening with your competition but to Ampad was acquired by also really understand your competition. The obvious methods, amongst many, are to group of investors conduct marketing research, read trade journals, and review press releases. You should also composed of an talk with your customers to see what you can find out about competition, but sometimes affiliate of Crescent Capital Investments, that can be a little dicey. himself, and another private investor. He also serves as Chairman of the company’s Board of When I talk about understanding your competition, I am talking about understanding how Directors. Previously at the helm of numerous your competition does things; how they react to competitive offerings or promotions; how fast industry-leading companies, Mr. Bermingham they are in reacting overall; how aggressive they are on pricing; and how marketing driven they brings more than 20 years’ experience in are. More so, I am a believer in understanding the actual people you are competing with. What guiding enterprises to new levels of are their personalities and how do they personally react to competitive offerings or promotions? performance. Most recently prior to joining When I was a National Sales Manager for a company in my earlier days, we had a Ampad, Mr. Bermingham held the positions of competitor that was led by a person who was completely irrational. Whenever we came out Chairman, President, and CEO of Centis, Inc., with a new sales promotion, this person would bounce off walls and berate his sales and a diverse multinational manufacturer and marketing people for letting us get the jump on them. An excellent tactic with sales and marketer of office, storage, and human marketing people! resources products. Prior to joining Centis, So when we would look to take market share from this competitor, we would go right at Mr. Bermingham successfully leveraged the them with sales promotions that were value-added promotions rather than price oriented. We potentials of two start-up companies, raising knew they would quickly meet a price-oriented promotion but had trouble reacting to a value- capital, forging key relationships, and added one. (If you are not familiar with this, value added means to buy something and get establishing the structure and direction that something else for free). Other competitors had management that would react in different ways, would pave the way for future growth and so we always kept that in mind when developing programs and product offerings. achievement. Among his many career Now for the spin. Do you know that you are the best source of competitive information on highlights in the role of President and CEO for companies serving the office products your company for your competitors. True! I can’t tell you how many times I have listened to industry, Mr. Bermingham successfully someone in a restaurant, airport, particularly on an airplane, or in other venues talk about their reorganized Smith Corona Corporation, company as if no one else is around. I especially enjoy hearing two or more people talk very restoring the company’s stability, profitability, negatively about their company and/or management. I also enjoy listening to people talk on and reputation. At Rolodex Corporation, he their cell phones about their company or management to others. refocused operations and a strategic vision Many years ago, I learned this lesson about you being the best source of competition for a dramatic turnaround in corporate information on your company. While flying back to Newark from the Consumer Electronics culture, and phenomenal increases in both Show in Las Vegas, I sat right behind the National Sales Manager and the National Marketing revenue growth and cashflow. Mr. Manager of my largest competitor. Throughout that flight, they reviewed everything a Bermingham’s expertise in leveraging competitor would want to know about their company strategy for the coming year. It was
ol 6 No 1 ol 6 No technology and optimizing resources for the amazing! I sat there with a note pad and wrote down everything they said. V business products/services markets has also A few months ago, I was flying from Dallas back to Newark and sat next to a person been deployed at industry giants, such as from Avon Products. This person was on her cell phone prior to the door being closed and, AT&T Consumer Products Group, and by in a loud voice, reviewed the company’s pricing strategy to include reviewing a long list of having served as the EVP of the Electronics their costs, product by product. Everyone within 10 rows could hear everything she said. I Group and President of the Magnetic Products January 2006 couldn’t believe it! Group, Sony Corporation of America. Mr. Bermingham served three years in the U.S. I continually coach our people on talking about the company in any public venue. Army Signal Corps with responsibility for Top Especially airports and aircraft, either directly to others or via cell phones. Restaurants Secret Cryptographic Codes and Top Secret follow closely behind. Those that concern me most are sales, marketing, product, and R&D Nuclear Release Codes. Earning a BA in people. These people have vast amounts of information that competition would love to have. Business Administration from Saint Leo So I coach and remind them the most. So we all have to think about this problem constantly University in Florida, Mr. Bermingham has and always be aware that you never know who is sitting around you.
Drug Delivery Technology Drug Delivery Technology also completed the Harvard University Listen carefully the next time you are in a public venue to the people talking around Graduate School of Business Advanced you. You will be amazed how much confidential information they relate to others on 82 Management Program. their company. ♦ Now open for business.
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