Executive Summary
This report captures the insights and expertise contained in presentations by
drug delivery technology industry leaders at three conferences organized by The
Center for Business Intelligence (CBI): Drug Delivery Systems, July 24-25, 2000;
Emerging Drug Delivery Technologies, April 5-6, 2001; and The Business
Case for Drug Delivery Systems, July 23-24, 2001. Each chapter in the first two
sections of this report is based on the material presented and also contains
editorial commentaries and figures. Each chapter in the third section focuses on
a specific drug delivery route or system and includes a technical overview by
the editor, Dr. Natalie Rudolph, followed by summaries of company-specific
presentations on their technologies.
Section I - Business Strategies and Market Drivers
Drug delivery (DD) technology deals now account for about one in seven
pharmaceutical deals, according to Fintan Walton of PharmaVentures,
Ltd. In Chapter 3, he describes ways to identify and evaluate
promising new technologies, considerations when preparing for a collaboration,
and the role and elements of feasibility agreements. The value of a new drug
deliver technology depends on how critical it is to the development of new drugs
that meet specific medical needs. A pharma company usually requests a
feasibility study to demonstrate how well a proposed new delivery technology
works for its own drug(s) before making a collaborative commitment. However, Mr.
Walton points out that if a collaboration is managed well and supported by
appropriate written agreements, it can set the stage for a long-term
relationship that builds value for both parties.
In Chapter 4, Christopher Dick of Elan Pharmaceutical
Technologies describes his company' s corporate strategy of forming a large
network of strategic alliances. He explains the use of feasibility studies,
pointing out that while they are generally "low risk," they are not "no
risk" : These studies entail the risk of giving away know-how, the risk of
failure ? And the risk of success. In the latter case, the pharma company may
license the technology and developed in-house or with a different partner. Mr.
Dick presents advantages and disadvantages of fully integrated internal drug
development programs from discovery through product launch ("mind-to-market"
programs), as well as advantages of full co-development and licensing
agreements. He also discusses life-cycle management, revenue sources from
development and licensing, and the role of technology transfer and joint
ventures.
Chapter 5 addresses market trends in the DD industry. According to Cornelis
Winnips of SkyePharma AG, there are new pressures on pharmaceutical
companies to increase their profits. DD companies need to understand how pre-
and post-launch profit drivers influence management and marketing decisions
about new drug products, and their impact on the establishment of drug
delivery-related partnerships between pharma and device companies. Dr. Winnips
lists technical and market factors that affect valuation of second-generation
products based on new delivery formulations. He points out advantages of
strategic partnerships to both types of companies to support his assertion that
drug delivery partnerships are the most effective way to develop successful
second-generation drugs.
Between 2000 and 2002, at least 13 major pharmaceuticals, accounting for
about $20.5 billion in annual sales, will have lost or will lose patent
protection. The loss of market exclusivity offers tremendous opportunities 1) to
generic drug companies to enter the market with lower-priced generic versions,
and 2) to drug delivery companies to develop second-generation drugs based on
proprietary delivery systems. In Chapter 6, Steven L. Hamilton of IOMED,
Inc., describes competitive and pricing pressures caused by patent
expirations and by consolidation within both the pharma and drug delivery
industries. In the face of these pressures, strategic alliances between these
two types of companies can be a way to enhance the value of both partners and to
help them meet their strategic needs. Such alliances can include mergers and
acquisitions, collaborations, licensing deals, marketing and co-promotion
agreements, and deals to expand patent protection.
In Chapter 7, J. Gregory Ford of RTP Pharma, Inc.,
describes a stepwise approach to building a drug delivery technology platform
into a successful commercial strategy. Short-term goals can be achieved by
establishing technology-development partnerships that help extend the life cycle
of a partner' s key product(s). This can expand to intermediate-term programs
that leverage the drug delivery technology platform to enable the development of
new drug products and to establish proprietary positions for both partners.
Ultimately, some companies will successfully develop their own pipelines of
proprietary products by applying drug delivery technologies to existing generic
drugs with formulation or delivery problems that limit their clinical
applications. These companies may seek partnerships or out-licensing agreements
for clinical testing, regulatory approval and market launch.
Development partnerships in the area of drug delivery technologies are
critical to Inhale Therapeutic Systems, Inc.' s long-term success, and
in Chapter 8, Ajit Gill explains how his company positions its
technology development programs to build value for itself and its partners. A
new drug delivery mode can rescue lagging drug sales for a secondary market
player and can convert a promising but impractical drug candidate into a
marketable product. Understanding the risks and benefits of developing drug
delivery technologies, both from the perspective of drug delivery and pharma
companies, can help technology companies select the best pharma alliance
partners and become desirable partners themselves. Mr. Gill also describes four
trends likely to shape the drug delivery industry in the near future.
In Chapter 9, Patrick Bols of PR Pharmaceuticals describes
inherent inequalities between small DD companies and their large pharmaceutical
partners in terms of the biblical story of David and Goliath. Both parties may
jockey for control over intellectual property, licensing rights, financial terms
and goals for future expansion. Even if they are not equal, however, small DD
companies and large pharma companies can establish successful relationships if
the parties focus on mutual strengths, synergistic capabilities, and strong
complementary needs that the companies can fill for each other. Dr. Bols also
details actions that pharma and drug delivery companies should and should not
take when establishing drug delivery development partnerships.
Pfizer Global Research Division represents the pharma side of a drug
delivery partnership: a large multi-national pharma company that in-licenses
drug delivery technologies from small companies to manage its R&D portfolio.
In Chapter 10, editor Dr. Natalie Rudolph summarizes Mak S. Jawadekar' s
overview of drug delivery technologies and partnerships from the perspective of
a large pharma company. This overview describes the criteria that a large
company uses to select new delivery systems for its drug products and defines
important factors when establishing and maintaining successful partnerships
between large and small companies. Large pharma companies are likely to have
large product and R&D portfolios containing drugs that are delivered by a
variety of routes with unique formulation or delivery challenges. Therefore,
pharma companies will form partnerships with multiple drug delivery partners to
gain access to the best delivery technology for each product.
Section II - Capitalizing on Outcomes Research
Michael Pollock of CareScience advocates the use of health
outcomes research to substantiate efficacy claims of pharmaceuticals and drug
delivery systems. Such studies can be used to promote and market drugs and their
delivery systems. Chapter 11 describes how managed care organizations
decide which new drugs and delivery systems they will reimburse, and how they
use information about clinical, economic and humanistic outcomes in this
decision-making process. Pharma or drug delivery companies should include health
outcomes studies as part of ongoing clinical trials and use the resulting data
to develop a convincing argument for the cost effectiveness of their new drugs,
devices or procedures.
Section III ? Advances in Drug Delivery Technologies
Chapter 12 discusses new developments in oral delivery. Oral
tablets are attractive for drug delivery because this mode of delivery is an
easy, convenient, noninvasive and familiar method of taking a drug. The
intestinal epithelium has a total surface area of about 200 m2, which is a very
large target for delivering drugs. However, some drugs cannot be delivered
orally because they are unstable in the stomach or inefficiently absorbed by the
intestine, because they are too short-lived in the circulation to be
therapeutically effective, or because their delivery must be timed to coincide
with the circadian rhythms of certain physiological events. The sections in this
chapter describe several approaches to increasing the efficiency of oral
delivery for special applications, including:
Chemical carriers to increase gastrointestinal absorption for oral delivery
of macromolecules, (Emisphere Technologies);
Rapid-dissolve waterless tablets, sustained-release oral delivery and
colon-specific drug delivery systems (Yamanouchi Pharma Technologies);
Three different technologies for fast-dissolve tablets, two of which use
effervescence to increase the rate of onset of drug activity (CIMA);
Oral controlled-release system (Penwest Pharmaceuticals Co.);
High-energy mechanochemical activation, which uses amorphous and
nanocrystalline composites to improve solubility (Eurand).
Chapter 13 addresses pulmonary delivery, which can be used to
administer drugs for both localized respiratory therapy and for noninvasive
systemic delivery of certain drugs that cannot be delivered orally. Although
metered dose inhalers (MDIs) have been used for almost 40 years, there is an
ongoing phaseout of the most common propellant because environmental concerns
necessitate new formulations and technologies. Following an overview of
pulmonary delivery of macromolecules by Michael Placke of Battelle Pulmonary
Technologies, the remaining parts of this chapter introduce new technologies
for pulmonary delivery, including:
Electrohydrodynamic devices for pulsatile pulmonary delivery (Battelle
Pulmonary Technologies);
Pocket-sized dry powder inhalers (DPI) that are breath-actuated and
motorized (Dura Pharmaceuticals, Inc.);
Breath-actuated metered-dose inhalers (MDI) and powder formulations
for dry powder inhalers (DPI) (SkyePharma AG);
Adaptive aerosol delivery that adjusts drug dosing to patients' breathing
patterns during delivery (Profile Therapeutics, Inc.);
Novel dry powder technology for small and portable MDI and PDI devices (Inhale
Therapeutic Systems, Inc.).
Transepithelial systems can be used to administer drugs across the skin (transdermal
delivery) or the mucosal lining of the nose and mouth (transmucosal
delivery). Chapter 14 describes the advantages of transepithelial
systems for convenient, noninvasive sustained drug delivery. Some of the newer
devices and formulations include:
Aqueous mist delivery of oral insulin (Generex Biotechnology Corp.);
Small patches for transdermal and transmucosal drug delivery (Noven
Pharmaceuticals, Inc.);
Novel films and polymers for topical or systemic delivery via the skin or
mouth (Atrix Laboratories);
Novel formulations to enhance nasal absorption of peptides and vaccines (West
Pharmaceutical Services);
Buccal patches for drug delivery across the mucosal lining of the cheek and
gum (3M Drug Delivery Systems);
Transdermal patches for sustained relief of chronic pain (3M Drug Delivery
Systems);
Needle-free drug and vaccine delivery by high-velocity dry powder injection (PowderJect
Pharmaceuticals plc);
Iontophoresis for transdermal treatment of acute local inflammation (IOMED,
Inc.);
Programmable iontophoresis system for active transdermal drug delivery (Vyteris,
Inc.);
Electrotransport for transdermal protein delivery (ALZA Corp.).
For drugs that are effective against their disease targets but limited by
acute systemic toxicity, targeted delivery by liposomes may provide the
best solution for efficacy and safety. After more than 20 years of development
efforts, liposomal drugs have been marketed for selected applications in cancer
and life-threatening systemic fungal infections, and more applications are in
development. Chapter 15 describes new technologies for stabilizing
liposomes. Extending their circulation time may enable the use of antibody and
ligand tagging for targeted liposomal delivery to distant or cryptic disease
sites in the body. Two examples of liposomal delivery systems are:
Liposomes for drugs to treat cancer (ALZA Corp.);
Liposomes that extend circulation time to deliver proteins (Genzyme Corp.).
In Chapter 16, Dr. Natalie Rudolph of Rudolph Biomedical
Consulting describes the development of polymers and microparticles for drug
delivery. These methods were originally designed to sustain drug delivery by 1)
prolonging the residence time of the drug in the circulation or 2) providing a
biodegradable or removable drug reservoir that releases the drug consistently
over an extended period of time. Among the subjects Dr. Rudolph covers in this
chapter are the "ideal" delivery system, types of polymers and polymer
particles used and particle life in vivo. She describes how polymer particles,
like liposomes, can be targeted to specific therapeutic sites by passive or
active mechanisms, and how the drug is released by polymer carriers. Because of
their large size and fragility, protein drugs present challenges for drug
delivery that can be met by the use of polymers. Also included are company
descriptions of two drug delivery systems that employ polymers:
Injectable microspheres made from biodegradable polymers and nanospheres for
oral delivery (PR Pharmaceuticals);
In situ implant depot for local or systemic drug delivery (Atrix
Laboratories Inc.).
The last chapter of this report, Chapter 17, summarizes two additional
technologies that have broad applications for improving drug delivery by
various routes. These drug delivery technologies include:
Gene-profiling technologies to characterize drug uptake by M cells in
Peyer' s patches (Digital Gene Technologies, Inc);
Insoluble drug delivery technologies for formulating water-insoluble drugs to
improve oral, injectable, topical and pulmonary delivery (RTP Pharma).
Table of Contents
1. Executive Summary
Part I - Business Strategies and Market Drivers
Part II - Capitalizing on Outcomes Research
Part III - Advances in Drug Delivery Technologies
2. Introduction
2.1 Goals of Alternative Drug Delivery
2.2 Methods of Alternative Drug Delivery
2.3 Sustaining and Controlling Drug Release
2.4 Adherence to Dosing Regimens
2.5 Timing of Remedication
2.6 Device-Related Medication Errors
2.7 The Business of Drug Delivery
2.8 References
3. Negotiating Licensing Agreements for Drug Delivery Technologies
3.1 Drug Delivery System Deals 17
3.2 Enabling versus Enhancing Technology
3.3 Criteria to Select the 'Right' Technology
3.4 Preparation for Collaboration
3.5 Feasibility Studies
3.6 Written Feasibility Agreements
3.7 Components of a Licensing Deal
3.8 Protection of Intellectual Property
3.9 The Art of Negotiation
3.10 How to Start the Process
3.11 Financial Terms and Royalties
3.12 Technology Valuation
3.13 Causes and Resolution of Valuation Differences
3.14 Case Study
3.15 Resolution of Deadlocks
3.16 Termination and Post-termination
3.17 Walking Away from a Deal
4. Strategic Partnerships at Elan Pharmaceutical Technologies
4.1 Strategic Partnering Deals
4.2 Feasibility Studies
4.3 Two Levels of Feasibility Studies for Drug Solubility
4.4 Development and Licensing Agreements
4.5 Life-Cycle Management
4.6 Lines of Revenue from Development and Licensing
4.7 Technology Transfer
4.8 Joint Ventures
4.9 Agreements for Drug Delivery Research
5. Market Trends in the Drug Delivery Industry
5.1 Opportunities for Non-CFC-Based Pulmonary Delivery Technologies
5.2 New Pressures on Drug Profits
5.3 Drug Product Life Cycle Management
5.4 Factors to Consider When Switching to Pulmonary Delivery
5.5 Partnerships to Develop Second-Generation Products Incorporating New DDTs
5.6 Issues in Structuring the DDT Deal
5.7 Typical Deal Structures
5.8 Questions & Answers
6. Consolidation Trends in the Drug Delivery Industry
6.1 Opportunity for Second-Generation Drug Products
6.2 Pharmaceutical Industry Issues
6.3 Other Aspects of Pharma Likely to Affect DDT Companies
6.4 Strategies to Remain Competitive
6.5 Consolidation in the DDT Industry
6.6 Value Enhancement Opportunities
6.7 Questions & Answers
7. Leveraging a Technology Platform into a Commercial Strategy
7.1 The Need for Solubilizing Technology Becomes Business Opportunity
7.2 Aspects of Developing an Internal Insoluble Drug Delivery Product Pipeline
7.3 Elements of a Life-Cycle Management Collaboration
7.4 Pros and Cons of Collaborations to Develop New Chemical Entities
7.5 Strategic Considerations for DDT Partnerships
8. Targeting a Pharmaceutical Product Pipeline
8.1 Payoffs from New Drug Delivery Technologies
8.2 Economics and Risks of New DDTs
8.3 Advantages and Disadvantages of DDT Alliances
8.4 Characteristics of the Best DD Alliance Partners
8.5 DDT Market Assessment
8.6 Trends in the Drug Delivery Industry
8.7 DDT/Pharma Company Requirements to Move Forward
9. Capitalizing on New Drug Delivery Technologies
9.1 The Good Business Climate for Drug Delivery Companies
9.2 Drug Delivery Companies and Big Pharma: A Case of David versus Goliath
9.3 Strong Points and Complementary Needs: The Ties that Bind
9.4 A Battle for Control: IP, Licensing and Financial Terms, and Company Goals
9.5 How to Play Ball with the Big/Little Guys
10. Novel Technologies and Partnering in R&D Portfolio Management
10.1 Strategic Use of Drug Delivery Systems
10.2 Selection of the Right Drug Delivery System
10.3 Considerations Regarding Internal versus External Development
10.4 Critical Factors for Partnerships
11. Health Outcomes Research to Position New Pharmaceutical Products
11.1 Perceptions of Health Care Value
11.2 Multidimensional Outcomes
11.3 Valuation of Outcomes Through Health Outcomes Research
11.4 Rationale for Outcomes Evaluation
11.5 Wants, Needs and Perspectives in Choosing Drugs and Devices
11.6 What Evidence is Needed-
11.7 Health Outcomes Research Strategy and Methods
11.8 How to Leverage the Evidence to Build Product Value
11.9 Market Access Challenges for Drug Delivery Companies
11.10 Recommendations for New Product Development
12. Oral Drug Delivery
12.1 Overview of Oral Drug Delivery
12.1.2 Controlled Release
12.1.3 Dysphagia
12.1.4 Drugs Best Suited to New Oral Delivery Systems
12.1.5 Specific Aspects of Oral Drug Delivery
12.2 Chemical Carriers to Increase Gastrointestinal Absorption of Therapeutic
Macromolecules
12.3 Controlled Drug Delivery Systems for Waterless Oral Delivery and
Colon-Specific Drug Delivery
12.4 Fast-Dissolve Tablets for Oral Drug Delivery
12.5 Oral Controlled Release for a Wide Variety of Drug Classes
12.5.1 Case Study: Cystrin
12.6 Amorphous and Nanocrystalline Composites to Improve Solubility for Oral
Delivery
13. Pulmonary Drug Delivery
13.1 Overview of Pulmonary Drug Delivery
13.1.1 Current Pulmonary Drug Delivery Devices
13.1.2 Next-Generation Pulmonary Technologies
13.1.3 Inhaled Biopharmaceuticals in Development
13.1.4 Specific Aspects of Pulmonary Drug Delivery
13.2 Pulmonary Delivery of Proteins, Peptides and Other Biomolecules
13.2.1 Respiratory Tract Anatomy
13.2.2 Calculation of Pulmonary Drug Doses
13.2.3 Effect of Respiratory Volume on Pulmonary Deposition
13.2.4 Technical Challenges for Pulmonary Protein Delivery
13.2.5 Design Factors for the Ideal Inhaler
13.2.6 Other Factors Affecting Pulmonary Delivery
13.3 Electrohydrodynamic Device for Pulmonary Delivery
13.3.1 Comparison with Other Inhalers
13.3.2 Product Pipeline
13.4 A Pocket-Size Motorized Dry Powder Inhaler
13.5 Breath-Actuated Metered Dose and Dry Powder Inhalers
13.5.1 A CFC-Replacing Breath-Actuated Metered Dose Inhaler (MDI)
13.5.2 Breath-Actuated MDI Products
13.5.3 Novel Dry Powder Inhaler
13.6 Inhaling Intelligently: Adaptive Aerosol Delivery
13.6.1 Approaches to Controlling Aerosol Doses
13.6.2 Adaptation to Patients' Breathing Patterns
13.6.3 Reliance on Compliance
13.7 Novel Dry Powder Technology
14. Transdermal and Transmucosal Drug Delivery
14.1 Overview of Transepithelial Drug Delivery
14.1.1 Transdermal Drug Delivery
14.1.2 Transmucosal Drug Delivery
14.1.3 Transcutaneous Immunization
14.1.4 Specific Transdermal and Transmucosal Delivery Systems
14.2 Aqueous Mist Delivery of Oral Insulin
14.3 Small Patches for Transdermal and Transmucosal Drug Delivery
14.4 Novel Films and Polymers for Transmucosal and Topical Transdermal Drug
Delivery
14.4.1 Bioerodible Mucoadhesive (BEMA) Film
14.4.2 Solvent Microparticle (SMP) Film
14.4.3 Mucocutaneous Absorption Gel (MCA) Technology
14.4.4 Biocompatible (BCP) System Technology
14.4.5 Atrix Laboratories' Strategic Alliances
14.5 Chitosan Formulations to Enhance Nasal Absorption of Peptides and Vaccines
14.5.1 Nasal Morphine for Pain Management
14.5.2 Nasal Influenza Vaccination
14.6 Buccal Technology for Transmucosal Drug Delivery
14.6.1 Drug Delivery Across Gum Mucosa
14.6.2 Applications of Buccal Drug Delivery
14.6.3 Patient Acceptance of Buccal Patches
14.7 Transdermal Drug Delivery for Chronic Pain
14.7.1 Clinical Management of Pain
14.7.2 Transdermal Delivery of Pain Medications
14.7.3 Transdermal Fentanyl Patches
14.8 Needle-Free Drug and Vaccine Delivery by High-Velocity Dry Powder Injection
14.8.1 Dry Particle Drug Delivery Through the Skin
14.8.2 Dry Powder Formulations
14.8.3 Protein and Peptide Delivery
14.8.4 DNA Vaccine Delivery
14.9 Active Transdermal Transport for Acute Local Inflammation and Ophthalmic
Disease
14.10 Programmable Iontophoresis System for Active Transdermal Drug Delivery
14.10.1 The Principle of Iontophoresis
14.10.2 Vyteris' s Iontophoretic System for Lidocaine/ Epinephrine
14.11 Macroflux Transdermal Technology for Protein Drug Delivery
14.11.1 Localized Macroflux Delivery
14.11.2 Combined E-Trans/Macroflux Delivery System
15. Liposomes for Drug Delivery
15.1 Overview of Liposomes for Drug Delivery
15.1.1 Clinical Applications of Liposome Technology
15.1.2 Types of Liposomes
15.1.3 Liposomal Targeting
15.1.4 Liposome Manufacture
15.1.5 Liposomal Drug and Protein Delivery Technologies
15.2 STEALTH Liposomes for Targeting Drugs to Sites of Disease
15.2.1 Pegylated Stealth Liposomes
15.2.2 Factors in Doxil Delivery
15.2.3 Stealth Liposomes Improve Safety
15.2.4 Stealth Camptothecin
15.2.5 Ligand-Targeted Stealth Liposomes
15.2.6 Rational Drug Selection to Optimize Liposome Technology
15.3 Extending Liposome Circulation Time for Protein Delivery
15.3.1 Liposome Production
15.3.2 Long-Circulating Liposomes
15.4 References
16. Polymers and Polymer-Based Particles for Drug Delivery
16.1 Optimizing Drug Delivery: Needs and Advantages
16.1.1 The 'Ideal' Delivery System
16.1.2 Types of Polymers and Polymer Particles
16.1.3 Polymer Particle Life In Vivo
16.1.4 Drug Targeting and Distribution
16.1.5 Drug Release from Polymer Carriers
16.1.6 Smart Polymers
16.1.7 Proteins as a Special Case
16.1.8 Systems In Development
16.1.9 Two Specific Polymer and Microparticle Technologies
16.2 TheraPhase and MediPhase for Sustained Drug Delivery
16.2.1 TheraPhase Injectable Microspheres
16.2.2 MediPhase Nanospheres for Oral Delivery
16.3 Novel Polymers for Topical Drug Delivery
16.3.1 Long-Lasting Local or Systemic Drug Delivery
16.3.2 Polymer Formulation for Periodontal Disease
16.3.3 Palliation for Prostate Cancer via a Polymer-Based Drug
16.4 For Further Reading
17. Other Drug Delivery Technologies
17.1 Drug Delivery Applications of the TOGA Gene Profiling Technology
17.1.1 TOGA: Total Gene Expression Analysis
17.1.2 Gene Profiling with TOGA
17.1.3 The Role of M Cells in Drug Delivery
17.2 Formulating Water-Insoluble Drugs to Improve Delivery
17.2.1 A Solution for Insolubility
17.2.2 Microparticles for Insoluble Drug Delivery (IDD)
17.2.3 IDD Microdroplets
17.2.4 Other IDD Formulations
17.2.5 Product Pipeline
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