Download role of lipid excipients in modifying oral and parenteral

ROLE OF LIPID
EXCIPIENTS IN
MODIFYING ORAL
AND PARENTERAL
DRUG DELIVERY
BASIC PRINCIPLES AND
BIOLOGICAL EXAMPLES
Edited by
KISHOR M. WASAN
University of British Columbia
Vancouver, British Columbia
A JOHN WILEY & SONS, INC., PUBLICATION
ROLE OF LIPID
EXCIPIENTS IN
MODIFYING ORAL
AND PARENTERAL
DRUG DELIVERY
ROLE OF LIPID
EXCIPIENTS IN
MODIFYING ORAL
AND PARENTERAL
DRUG DELIVERY
BASIC PRINCIPLES AND
BIOLOGICAL EXAMPLES
Edited by
KISHOR M. WASAN
University of British Columbia
Vancouver, British Columbia
A JOHN WILEY & SONS, INC., PUBLICATION
Copyright © 2007 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
Role of lipid excipients in modifying oral and parenteral drug delivery : basic principles and biological
examples / [edited by] Kishor M. Wasan.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-471-73952-4 (cloth)
ISBN-10: 0-471-73952-9 (cloth)
1. Lipids—Therapeutic use. 2. Excipients. 3. Drugs—Dosage forms. I. Wasan, Kishor M.
[DNLM: 1. Excipients—therapeutic use. 2. Administration, Oral. 3. Drug Compounding—
methods. 4. Drug Delivery Systems. 5. In-fusions, Parenteral. 6. Pharmaceutical Solutions.
QV 800 R745 2007]
RS201.E87R65 2007
615′.7—dc22
2006019129
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
CONTENTS
PREFACE
vii
CONTRIBUTORS
ix
CHAPTER 1
INTERACTION OF DRUG TRANSPORTERS WITH EXCIPIENTS
1
K. Sandy Pang, Lichuan Liu, and Huadong Sun
FORMULATION ISSUES AROUND LIPID-BASED ORAL AND
PARENTERAL DELIVERY SYSTEMS
CHAPTER 2
32
Seong Hoon Jeong, Jae Hyung Park, and Kinam Park
LIPID-BASED PARENTERAL DRUG DELIVERY SYSTEMS: BIOLOGICAL
IMPLICATIONS
CHAPTER 3
48
Vladimir P. Torchilin
PRINCIPLES IN THE DEVELOPMENT OF INTRAVENOUS LIPID
EMULSIONS
CHAPTER 4
88
Joanna Rossi and Jean-Christophe Leroux
PROTEIN ADSORPTION PATTERNS ON PARENTERAL LIPID
FORMULATIONS: KEY FACTOR DETERMINING THE IN VIVO FATE
CHAPTER 5
124
Rainer H. Müller and Torsten M. Göppert
NANOPARTICLE TARGETING FOR DRUG DELIVERY ACROSS THE
BLOOD–BRAIN BARRIER
CHAPTER 6
160
James Egbert, Werner Geldenhuys, Fancy Thomas, Paul R. Lockman,
Russell J. Mumper, and David D. Allen
LIPID-COATED PERFLUOROCARBON STRUCTURES AS
PARENTERAL THERAPEUTIC AGENTS
CHAPTER 7
170
Evan C. Unger, Terry O. Matsunaga, and Reena Zutshi
INDEX
197
v
PREFACE
The primary roles of traditional excipients were to bind and provide bulk to the
dosage form, to facilitate or control drug release from the excipient matrix, and to
facilitate product manufacturing on high-speed, automated, production equipment.
However, lipid excipients, unlike their traditional counterparts, have the ability to
solubilize hydrophobic drugs within the dosage form matrix. This often results in
the case of oral drug delivery, improved drug absorption, which is primarily mediated by a reduction in the barriers of poor aqueous solubility, and slow drug dissolution rate in the gastrointestinal (GI) fluids. Some of these excipients also have
desirable self-emulsifying properties, readily forming fine dispersions of lipidsolubilized drug in the aqueous contents of the GI tract and creating optimal conditions for absorption.
The pivotal activities involved in the development of any oral dosage form (a
conventional solid or lipid-based formulation) include: (1) physiochemical and biopharmaceutical understanding of the drug substance, which would guide initial
excipient selection and subsequent design of a prototype dosage form; (2) product
stability and dissolution testing, which demonstrates physical and chemical stability of the drug substance during the shelf-life of the product; (3) formulation scaleup to production size batches; (4) development of a discriminating dissolution test
method, to provide assurance of product quality and batch-to-batch consistency; and
(5) justification of the formulation rationale to regulatory agencies. However,
although the pivotal activities associated with the development of a lipid-based
formulation are similar to those for a conventional oral solid, the manner in which
pharmaceutical scientists achieve these goals will be different. The ability of
pharmaceutical scientists in re-defining these pivotal development activities for
lipid-based formulations, both oral and parenteral, may in fact determine the future
success of this technology.
A number of important questions will need to be more fully addressed in order
to provide pharmaceutical scientist formulators with consistent guidelines for the
development of novel oral and parenteral lipid-based formulations, e.g. what role
will dissolution testing play in the development and evaluation of liquid and semisolid lipid-based dosage forms? Should dissolution testing be performed at all? If
so, what parameters are important and how will the data be interpreted? How is
stressed stability testing performed on semi-solid dosage forms, which melt at elevated temperatures? Will the physical state of drugs in matrices change upon aging
and how might this impact drug delivery? What types of chemical incompatibilities
are peculiar to lipid excipients? How will these excipients affect the integrity of
gelatin capsules?
vii
viii
PREFACE
The availability of a wide variety of pharmaceutical grade lipid excipients has
coincided with a recent advance in encapsulation technology, which now allows hard
gelatin encapsulation of both liquid and semi-solid formulations. This advance,
along with the fact that almost half of all new chemical entities fit the category of
‘poorly water soluble’ has created a window of opportunity for the rapid introduction of oral lipid-based drug formulations into the marketplace.
As we begin to unravel the intricacies of the GI processing of lipid excipients,
further improvements in the performance of lipid-based delivery systems can be
expected, e.g. an increasing body of evidence has shown that certain lipids are
capable of inhibiting both pre-systemic drug metabolism and P-glyoproteinmediated drug efflux by the gut wall. And it is well known that lipids are capable
of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This book addresses not only formulation issues, but also these physiological and biopharmaceutical aspects of oral
lipid-based drug delivery.
As a new and evolving discipline, lipid-based drug delivery has attracted considerable attention from academia to industry. Over the past few years, academic
and industrial interests in this area have been evident from the increase in national
and international symposiums and workshops on many different aspects of lipidbased drug delivery systems. Many universities are now offering comprehensive
courses in lipid-based drug delivery systems. Although these courses are highly
effective, frequent requests for a standard textbook on oral lipid-based drug delivery systems prompted me to this current project in editing a book on lipid-based
drug delivery. At the present, there is no comprehensive textbook available and
various graduate level courses on this interesting topic were taught by professors
with materials gathered from diverse sources. To satisfy this urgent need, we plan
to assemble a group of experienced investigators/educators who are on the frontline
of pharmaceutical sciences to develop such a textbook. This textbook is intended
for both pharmaceutical scientists and trainees in the field of drug delivery, formulation development, and drug discovery, and presents fundamental principles and
biological examples in the use of lipid excipients to develop both oral and parenteral
drug delivery systems.
Kishor M. Wasan
CONTRIBUTORS
David D. Allen, RPh, PhD, FASHP
Dean and Professor, Northeastern Ohio Universities, College of Pharmacy,
Rootstown, Ohio, USA
James Egbert
Northeastern Ohio Universities, College of Pharmacy, Rootstown, Ohio, USA
Werner Geldenhuys
Northeastern Ohio Universities, College of Pharmacy, Rootstown, Ohio, USA
Torsten M. Göppert
Department of Pharmaceutical Technology, Biotechnology and Quality Management
The Free University of Berlin, Germany
Seong Hoon Jeong
Departments of Pharmaceutics and Biomedical Engineering, Purdue University,
West Lafayette, Indiana, USA
Jean-Christophe Leroux
Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of
Montreal, Canada
Paul R. Lockman
Northeastern Ohio Universities, College of Pharmacy, Rootstown, Ohio, USA
Terry O. Matsunaga, PharmD, PhD
ImaRx Therapeutics, Inc., Tucson, Arizona, USA
Rainer H. Müller
Professor, Department of Pharmaceutical Technology, Biotechnology and Quality
Management, The Free University of Berlin, Germany
Russell J. Mumper
Northeastern Ohio Universities, College of Pharmacy, Rootstown, Ohio, USA
K. Sandy Pang
Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada
x
CONTRIBUTORS
Jae Hyung Park
Departments of Pharmaceutics and Biomedical Engineering, Purdue University,
West Lafayette, Indiana, USA
Kinam Park, PhD
Purdue University, School of Pharmacy
West Lafayette, Indiana, USA
Joanna Rossi
Faculty of Pharmacy, University of Montreal, Canada
Fancy Thomas
Northeastern Ohio Universities, College of Pharmacy, Rootstown, Ohio, USA
Vladimir P. Torchilin
Professor, Department of Pharmaceutical Sciences
Northeastern University, Boston, Massachusetts, USA
Evan C. Unger, MD
ImaRx Therapeutics, Inc., Tucson, Arizona, USA
Reena Zutshi, PhD
ImaRx Therapeutics, Inc., Tucson, Arizona, USA
CHAPTER
1
INTERACTION OF
DRUG TRANSPORTERS
WITH EXCIPIENTS
K. Sandy Pang, Lichuan Liu, and Huadong Sun
1.1
INTRODUCTION
1.2
INTESTINAL ABSORPTIVE TRANSPORTERS
1.3
INTESTINAL EFFLUX TRANSPORTERS
1.4 MODULATION OF DRUG TRANSPORTERS BY EXCIPIENTS AND
SURFACTANTS
1.5
1.1
CONCLUSION
INTRODUCTION
The intestine is the most important site for drug absorption and regulates the extent
of orally administered drug that reaches the circulation. Oral drug absorption or
bioavailability relates to the net amount of dose absorbed, and occurs mainly via the
small intestine where the surface area is much greater than that in the stomach. The
first major obstacle is crossing the intestinal epithelium and survival from intestinal
and liver metabolism. There are essentially two routes: the paracellular and transcellular pathways in which compounds permeate across the intestinal membrane.
For small hydrophilic, ionized compounds, absorption may occur via the paracellular pathway. The transcellular transport processes include passive diffusion, membrane permeation via transporters that are primary, secondary, and tertiary in terms
of ATP requirements, and include co-transporters (symport) or exchangers (antiport)
(Figure 1.1). Transcellular absorption of drugs occurs from the lumen to blood, and
necessitates uptake across the apical membrane, and then the drug exits across the
basolateral membrane.
Lipophilic drugs readily diffuse across the apical membrane from the lumen,
and their subsequent passage across the basolateral membrane into blood is also
by diffusion. Within the small intestine, phase I and II enzymes are present to
Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery, Edited by Kishor M. Wasan
Copyright © 2007 John Wiley & Sons, Inc.
1
2
CHAPTER 1
INTERACTION OF DRUG TRANSPORTERS WITH EXCIPIENTS
Figure 1.1 Schematic presentation of modes of drug transport (upper) and
energy-dependent transport.
effect drug removal in a competitive fashion, and these also compete with
efflux transporters at the apical and basolateral membranes [1, 2]. Although the
activities of these drug-metabolizing enzymes of the small intestine are usually
lower than those of the liver, the intestine is a portal tissue that regulates the level
of substrate reaching the liver. A thorough understanding of the interactions between
transport and metabolism in the small intestine is achieved only through the understanding that transporters and enzymes are pathways competing for the substrate
[1–4].
At the apical membrane of the intestine, solute carrier transporters (SLCs)
mediate the absorption of chemical entities from the lumen, and then the drugs exit
at the basolateral membrane to enter the circulation [5–11]. The membrane transporters include the SLC transporter family and the ATP-binding cassette (ABC)
transporter family (see www.gene.ucl.ac.uk/nomenclature). Currently, the SLC
transporter family includes about 50 families and more than 360 transporter genes.
A transporter is assigned to a specific SLC family if at least 20–25% of its amino
acid sequence identifies with other members of that family. The SLC transporters
are involved in uptake, whereas the ABC transporters are efflux proteins located at
the apical membrane of the small intestine to redirect the absorbed drug to re-enter
the lumen (Figure 1.2). Both transporters and enzymes are under regulation of
orphan nuclear receptors (see the literature [12–25]). These include the aryl hydro-
1.2 INTESTINAL ABSORPTIVE TRANSPORTERS
3
Figure 1.2 Intestinal apical absorptive (left) and efflux (middle) transporters, and
basolateral transporters of solutes and absorptive and efflux transporters of cholesterol
(left panel).
carbon receptor (AHR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid X-receptor (FXR), the nuclear factor-E2 p45-related factor 2
(Nrf2), hepatocyte nuclear factor 1α and 4α HNF-1α and HNF-4α, liver receptor
homolog 1 (LRH-1], liver X-receptor (LXR), small heterodimer partner-1 (SHP-1),
the glucocorticoid receptor (GR) and the vitamin D receptor (VDR).
The regulation of both transporters and enzymes by nuclear orphan receptors
and the associated complexities, such as coordinate regulation and cross-talk, are
under intense investigation [18, 22]. However, the topic of regulation of transporters
and enzymes by nuclear receptors is beyond the scope of this chapter, the focus of
which reviews some of the transporters involved in drug disposition. In addition the
modulation of the transporters in the intestine by excipients is described.
1.2
INTESTINAL ABSORPTIVE TRANSPORTERS
The intestine is known to absorb drugs as a result of the increased surface area caused
by the presence of villi and microvilli. The existence of various transporters on the
apical membrane has been reviewed [8–11]. Nutrients such as amino acids are
broken down from protein by peptide digestion, and are absorbed via by a set of
amino acid transporters that differ with regard to sodium dependence, substrate
specificity, driving force, and genetic classification. Vectorial transport is ensured by
other basolateral amino amid transporters. Various transporters exist for nutrients: