Rainer H. Miiller, Simon Benita,
`Bernhard H. L. Béhm
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`Emulsions and Nanosuspensions
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`for the Formulation of Poorly
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`Soluble Drugs
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`Emulsions and
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`Nanosus ensions
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`for Formulation
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`of Poorly Soluble Drugs
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`edited by
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`Prof. Dr. rer. nat. Rainer H. Miiller
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`Department of Pharmaceutics, Biopharmaceutics and Biotechnology
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`Free University of Berlin
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`Prof. Dr. rer. nat. Simon Benita
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`School of Pharmacy
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`The Hebrew University ofJerusalem
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`Bernhard H. L. Bohm
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`Department of Pharmaceutics, Biopharmaceutics and Biotechnology
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`Free University of Berlin
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`The book chapters are based on the invited lectures and communications
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`presented at the Colloidal Drug Carriers - cdc — 31-d Expert Meeting
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`Berlin (Germany) 29 — 31 May 1997
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`(main organizers: Prof. Dr. R.H. Miiller, Dr. W. Mehnert)
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`188 Figures and 34 Tables
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`III Scientific Publishers Stuttgart 1998
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`The use of general discriptive names, trade names, trademarks, etc. in a publication, even if not
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`regulations.
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`Die Deutsche Bibliothek ~ CIP—Einheitsaufnahme
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`Emulsions and nanosuspensions for the formulation of poorly
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`soluble drugs : based on the invited lectures presented by the authors
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`at the colloidal drug carriers — CDC — 3rd expert meeting, Berlin
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`(Germany), 29-31 May 1997 / ed. by Rainer H. Muller
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`organizers: R. H. Muller ; W. Mehnert). — Stuttgart : Medpharm
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`Scientific Publ., 1998
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`ISBN 3—88763-069-6
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`All right reserved. No part of this publication may be translated, reproduced, stored in a retrieval
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`system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, micro-
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`filming, recording or otherwise, without permission in writing from the publisher.
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`© 1998 medpharm GmbH Scientific Publishers, Birkenwaldstrafie 44, D-70191 Stuttgart
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`Printed in Germany
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`Druck: Hofmann, Schorndorf
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`Umschlag: Atelier Schafer, Esslingen
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`

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`Preface
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`Colloidal or generally particulate delivery systems are increasingly considered to solve
`delivery problems — ranging from solubility problems, reduction of drug side effects
`(e.g. Diazepam) over controlled release to site-specific delivery. In Europe a meeting
`series has been established dealing especially with these delivery systems - the ,,Colloi-
`dal Drug Carriers - cdc - Expert Meetings“. The first meeting was in Berlin in 1995. The
`3"’ meeting in Berlin in 1997 was focused on the problem of delivering poorly soluble
`drugs.
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`Poorly soluble drugs are a challenge to drug formulation work and an increasing prob-
`lem because especially many newly developed drugs are poorly soluble — very often
`simultaneously in aqueous and in organic media. This requires new approaches to over-
`come this problem.
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`A trendy, fashionable delivery system for drugs poorly soluble in water are liposomes
`— despite the fact that liposomes bear many problems ranging form physical stability
`to the chemical stability of the cxcipicnts used. People tend to prefer sophisticated
`delivery systems, especially in our technology orientated world. However, why try to
`use a sophisticated and expensive delivery system while relatively simple delivery sys-
`tems are available and can do the job?
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`Little or limited attention has been focused during the last years on two delivery systems
`with principally large potential.
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`A more simple but efficient delivery system are the traditional o/w-emulsions used in
`parenteral nutrition since the fifties. They are toxicologically acceptable by the regula-
`tory authorities (e.g. FDA, BfArM in Germany).
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`Logo of the ,,ColloidaI Drug Carriers ~ cdc» Expert Meetings“,
`3rd Meeting held 29-31 May 1997 in Berlin“ (copyright by RH. Miiller, Berlin)
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`Large scale production by high pressure homogenization on established production
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`lines available in industry is possible. Large scale production is the prerequisite for the
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`introduction of products to the pharmaceutical market. The book reviews possibilities,
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`limitations and future perspectives of emulsions as drug carriers considering also tech-
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`nology from other than pharmaceutical industry (i.e. food industry). Aspects such as
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`distribution and metabolism of emulsions and their safety and tolerability are also cov-
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`ered including the preparation of physically stable multiple emulsions (in cosmetics).
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`Another system for the formulation of poorly soluble drugs are hydrosols by Sucker —
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`drug nanoparticles prepared by precipitation. However, they are limited to drugs being
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`soluble at least in one medium to perform the precipitation step. The book presents the
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`next development step — the nanosuspensions (Diss0CubesTM). This technology can be
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`applied also to drugs being insoluble simultaneously in aqueous and in organic media.
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`The contributions present the production technology (simple high pressure homogeni-
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`sation step using equipment even accepted in production lines for parenterals), explain
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`the special dissolution properties, i.e. increased saturation solubility and increased dis-
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`solution velocity (theory) and cover the possible applications. The differences to other
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`drug nanoparticles (e.g. hydrosols, NanoCrystalsT ) are discussed.
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`Dispersion techniques are an essential technology for the preparation of emulsions and
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`nanosuspensions but also other carrier systems like liposomes. The book presents high
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`pressure production techniques — theory and examples of application. The theory of
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`high pressure homogenization is explained in detail. High pressure extrusion is presen-
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`ted for its main application area — the preparation of liposomes. Size measurements are
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`the most important tool to judge the efficiency of a dispersion process. Many methods
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`require dilution of the samples prior to measurement which might change the sample
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`properties. In this book a measuring technology is presented allowing size analysis in
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`concentrated dispersions.
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`Deliver
`systems similar to the emulsions, the solid lipid nanoparticles (SLNTM, Lipo-
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`pearlsT ) are also presented including aspects of the interaction between particulate
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`carriers and the body proteins. Protein analysis is performed by two—di1nensional poly-
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`acrylamide gel electrophoresis (2-D PAGE, ,,-DE“). The protein adsorption patterns can
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`provide not only information about the in vivo organ distribution of i.v. injected carriers
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`(emulsions, nanoparticles) but also about the biocompatibility of surfaces (e.g. comple-
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`The book is not only addressed to scientists in pharmaceutical development but also to
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`colleagues in other fields, that means field dealing with colloidal systems, especially
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`emulsions and suspensions, or dispersion technology in general.
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`Berlin and Jerusalem, 4 August 1998
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`Rainer H. Miiller, PhD
`Professor at the
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`Free University of Berlin
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`Simon Benita, PhD
`Professor at The Hebrew
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`University of Jerusalem
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`Bernhard H.L. Biihm
`Scientist at the
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`Free University of Berlin
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`

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`Preface
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`» -...-. ... . ,. .-
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`,t.-
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`.« ..-.- ».»»t..»..—,.:r;.-.-.-;-.- «~..-.~..- -.»._~...v.»..-..~.»,«».~‘.».:.a--.,._ v\'
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`.-..<. -.-;..« t.\-I ~;.......
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`-.-.4
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`INTRODUCTION
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`1 Poorly soluble Drugs,
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`a Challenge in Drug Delivery
`Prof. Dr. P. P. Speiser, ETH-Ziirich
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`1.1 Notion .............................................................................................................. .. 15
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`1.2 Pharmaceutical concepts
`1.2.1 Liquid colloidal solutions
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`1.2.2 Solid dispersions
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`1.2.3 Solvent evaporation
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`1.2.4 Solvent deposition
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`1.2.5 Solid matrix incorporation
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`1.2.6 Drug interactions
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`1.2.7 Adsorption and Inclusion
`1.3 Stabilization ...................................................................................................... 18
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`1.4 Pharmacotechniques ........................................................................................ 18
`1.4.1 Overview
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`1.4.1.1
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`Solvatation
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`1.4.1.2 Microniaation
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`Instant evaporation
`1.4.1.3
`1.4.1.4 Drug deposition
`1.4.1.5
`Solid solutions
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`1.4.1.6 Complexation
`1.4. 1.7
`Solid Initticarriers
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`............................................................................ .. 19
`1.4.1.8 Liquid mim‘carrier.s
`1.4.2 Short description of some pharmacotechniques
`............................................. 20
`1.4.2.1
`Solubilization ..................................................................................... .. 20
`1.4.2.2 Micronization ..................................................................................... .. 20
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`Precipitation
`1.4.2.3
`1.4.2.4 Melting and instant cooling ............................................................... .. 21
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`4
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`TABLE OF CONTENTS
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`1.4.2.5
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`Injection moulding .... ..
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`1.4.2.6
`Spraying ............................................................................................. .. 21
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`1.4.2.7 Lyophilization .................................................................................... .. 22
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`1.4.2.8 Complexes
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`Solid rninicarriers
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`1.4.2.9
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`1.4.2.10 Vesicularminicarriers
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`1.5 Summary ......................................................................................................... .. 26
`1.6 References
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`EMULSIONS
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`2 Emulsions as drug carriers — possibilities, limitations
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`and future perspectives
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`Shmuel H. Klang, Marina Parnas and Simon Benita, Department of Pharmaceutics,
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`Schoolof Pharmacy. The Hebrew University of Jerusalem
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`Introduction ..................................................................................................... .. 31
`2.1
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`2.2 Possibilities
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`2.2.1 Emulsions intended for parenteral administration ....................................... .. 33
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`2.2.1.1 Current status of marketed em.ulsz‘ons
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`2.2.1.2
`Emulsions under current clinical evaluation
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`2.2.1.3 Medicated enmlsions under preclinical evaluation ........................... .. 45
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`2.2.2 Non—parentera1 emulsion formulations
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`2.2.2.1
`Topical Delivery ................................................................................ .. 48
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`2.2.2.2 Oraldelivery ....................................................
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`2.2.2.3 Ocular Delivery ................................................................................. .. 49
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`2.3 Limitations
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`2.4 Perspectives
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`2.4.1 Long-circulating emulsions
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`2.4.2 Positively-charged submicron emulsions
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`2.5 References
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`3 Multiple Emulsions in Cosmetics
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`J. Nielsen, S.H. Gohla, Beiersdorf AG. Hamburg
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`Introduction ..................................................................................................... .. 67
`3.1
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`3.2 History ............................................................................................................. .. 67
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`3.3 Manufacturing methods and current technologies
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`3.3.1 Two step technology
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`3.3.2 One step technology
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`3.3.2.1 Gel network derived dropletformation .............................................. .. 71
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`3.3.2.2 Direct emulszficdtion ( ,,0leos0me“ formation)
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`3.3.2.3
`Formation of intermediate multiple droplets during phase-inversion . 72
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`3.3.2.4 Partial-Phase Solu-Inversion Technology (PPSIT):
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`3.4 Stability control and characterization of multiple emulsions
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`3.5 Cosmetic Applications
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`3.6 Summary ......................................................................................................... .. 77
`3.7 Literature ......................................................................................................... .. 78
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`4 Emulsions in food products: preparation, stabilization and
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`applications
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`Willem van Nieuwenhuyzen, Eridania Béghin—Say Research & Development Centre,
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`Central Soya/Stern Lecithin, Vilvoorde, Belgium
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`Introduction .................................................................................................... .. 79
`4.1
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`4.2 Basics of food production ............................................................................. .. 80
`4.3 Food emulsifiers
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`4.3.1 Lecithin
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`4.3.1.]
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`Production of lecit/tins
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`4.4 Preparation and formulation of food emulsions
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`4.5 Principles of food emulsion stability ........................................................... .. 90
`4.5.1 Effect of pliospholipids
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`4.5.2 Phospholipids in nanoemulsions
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`4.6 Applications .................................................................................................... .. 93
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`4.6.1 Margarine/Low fat spreads
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`4.6.2 Mayonnaise/Dressings
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`4.6.3 Dairy instant products
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`4.6.4 Chocolate
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`4.6.5 Flavor/Antioxidant encapsulation
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`4.7 Conclusion ...................................................................................................... .. 99
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`4.8 Literature ......................................................................................................... .. 99
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`5 Drug release and interfacial structure in emulsions
`C. Washington, Department of Pharmaceutical Sciences, University of Nottingham
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`101
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`5.1
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`5.2 Measurement of drug release
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`Introduction .................................................................................................. .. 101
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`TABLE OF CONTENTS
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`5.3
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`...................................... .. 108
`Sma1l—angle neutron scattering from emulsions
`5.3.1 Data analysis
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`5.3.2 Effect of electrolytes
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`5.3.3 Effect of temperature
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`5.4 Conclusions
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`5.5 Acknowledgements ..................................................................................... .. 116
`5.6 References
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`Distribution and Metabolism of Emulsions In Vivo
`M. Adolph, Krankenhauszweckverband, Institut fur Aniisthesiologie und operative
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`Sportmedizin, Augsburg, Germany
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`6.1 Metabolism of triglyceride—rich particles
`1 19
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`6.2 Metabolism of phospholipid-rich particles
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`6.3 Lipid emulsions and reticuloendothelial system function ...................... .. 122
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`6.4 Hepatic complications during long—term parenteral nutrition ................ .. 123
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`6.5 Lipid emulsions and cellular immunity .................................................... .. 124
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`6.6 Peroxidation in parenteral nutrition ........................................................... .. 125
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`6.7» Lipid emulsions and drug delivery ............................................................ .. 126
`6.8 Conclusion
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`6.9 References
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`Safety and tolerability of intravenously administered
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`phospholipids and emulsions
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`Michael J. Parnham, Pharmacological Institute for the Natural Sciences, Frankfurt
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`Introduction
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`7. 1
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`7.2 Safety of parenteral phospholipids
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`7.3
`Interactions of phospholipids with transported drug ............................... .. 134
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`7.4 Safety of emulsions
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`7.5 Tolerability of mixed micelles
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`7.6 Reduction of drug toxicity by formulation in lipid emulsions
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`7.7 Special patient consideration ...................................................................... .. 137
`7.8 Conclusions
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`7.9 References
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`TABLE OF CONTENTS
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`7
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`NANOSUSPENSIONS
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`8 Dissolution properties of poorly soluble drugs:
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`Theoretical background and possibilities to improve the
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`dissolution behaviour
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`Christer Nystriim, Department of Pharmaceutics, Uppsala University, Sweden
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`Introduction .................................................................................................. .. 143
`8.1
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`8.2 Dissolution theory and enhancement of dissolution rate ......................... .. 144
`8.2.1
`Increase in solubility
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`8.2.2 Decrease in effective diffusional distance
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`Increase in effective dissolution surface area
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`8.3 Formulations for instant dissolution of practically insoluble drugs
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`8.3.1 Ordered mixtures
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`8.3.2 Solid dispersions
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`8.4 Conclusions
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`8.5 References
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`8.2.3
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`9 Nanosuspensions
`Rainer H. Miiller, Bernhard H.L. Btihm, Institute of Pharmaceutical Technology,
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`Free University of Berlin
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`Introduction ............................................................................................... .. 149
`9.1
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`9.2 Production of nanosuspensions
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`9.3 Properties of nanosuspensions .................................................................... .. 153
`9.3.]
`Size and width of size distribution of bulk population .... ..
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`9.3.2 Content of microparticles in nanosuspensions
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`9.3.3 Saturation solubility
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`9.3.4 Dissolution velocity .................................................................................... .. 158
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`9.3.5 Electron microscopy of nanosuspensions
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`9.3.6 Structure of nanosuspensions
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`9.3.7 Physical stability of aqueous nanosuspensions
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`9.3.8 Lyophilization
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`9.3.9 Spray drying of nanosuspensions
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`9.4 Large scale production of nanosuspensions .............................................. .. 166
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`9.5 Regulatory aspects
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`9.6 Nanosuspensions versus other highly dispersed systems ........................ .. 171
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`9.7 Perspectives .................................................................................................. .. 172
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`9.8 References
`L
`if:a.w@"*’”//”'~"”
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`DISPERSION TECHNIQUES
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`10 The theory of high—pressure homogenization
`Dipl.-Ing. S. Jahnke, APV Homogeniser GmbH, Lijbeck
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`10.1 The Principle of High—pressure Homogenization ...........................
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`10.2 The Flow Conditions in the Homogenizing Valve
`10.2.1 Pressure Reduction through Friction in the Homogenizing Valve Gap
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`10.2.2 Frictional Pressure Loss
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`10.2.3 Total Pressure Loss in the Homogenizing Valve ....................................... ..
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`10.2.4 Description of the Pressure Course in the Homogenizing Valve Gap ....... ..
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`10.3 Specific Amount of Energy and Temperature Load ............................... .. 184
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`10.4 Mechanisms causing the Comminution in the Homogenizing Valve
`10.4.1 Comminution in the Laminar Shear Field
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`10.4.2 Comminution in the Turbulent Shear Field
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`10.4.3 Cavitation
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`10.5 Influence of Important Product
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`10.5.1 Viscosity of the Disperse Phase
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`10.5.2 Concentration of emulsifier agent
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`10.5.3 Emulsifier Surface Occupation Kinetics and Oil Concentration
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`10.5.4 Particle Size of Premix
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`10.5.5 Homogenizing Pressure and Number of Passes
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`10.6 Homogenizers in Practical Use .................................................................. .. 197
`10.6.1 Division, capacity ranges
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`10.6.2 Requirements for High-pressure Homogenizers for the Practical Use in
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`10.6.3 Factors influencing the Selection of Homogenizing Valves
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`10.7 Summary ...................................................................................................... .. 199
`10.8 Literature
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`TABLE OF CONTENTS
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`9
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`11 Manufacture of emulsions by means of high~pressure
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`homogenization: Influence of homogenization parameters, oils
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`and surfactants
`Thomas Bock, Peter Kleinebudde and Bernd W. Miiller, Boehringer Ingelheim Pharma
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`KG, Biberach, Germany
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`Christian Albrechts Universitat, Kiel, Germany
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`11.1 Study design ................................................................................................. .. 203
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`11.2 Emulsions containing 20% soya oil and 1.5% Lipoid S75 ..................... .. 205
`11.2.1 Effect of homogenization parameters on D50 values
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`11.2.2 Effect of homogenization parameters on D99 values
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`11.2.3 Effect of homogenization parameters on PCS radii
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`11.2.4 Summary of results
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`11.3 Emulsions containing 10% soya oil and 1.5% Lipoid S75 ..................... .. 218
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`11.4 Emulsions containing 10% soya oil and 0.75% Lipoid S75 ................... .. 220
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`11.5 Comparison of results obtained with emulsions
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`11.5.1 Selection of homogenization conditions
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`11.5.2 Homogenization at 400 bar/ 26°C ............................................................. .. 222
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`11.5.3 Homogenization at 800 bar/26°C ............................................................. .. 224
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`11.5.4 Homogenization at 400 bar/ 46°C ............................................................. .. 226
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`11.5.5 Homogenization at 800 bar / 46°C ............................................................. .. 227
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`11.5.6 Comparison of emulsions manufactured at optimal temperatures
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`and pressures
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`11.5.7 Summary of results
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`11.6 Flow diagram for optimising the manufacture of emulsions
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`11.7 References
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`12 Optical Reflectance Measurement (ORM) - A novel approach
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`for particle size measurement on highly
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`concentrated dispersions
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`Rudolf Daniels, Roland Karwoth, Department of Pharmaceutical Technology, TU
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`Braunschweig, Germany
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`Melfitechnik Schwartz GmbH, Dusseldorf, Germany
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`12.1 Introduction ............................................................................................... .. 237
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`12.2 Principle of operation .................................................................................. .. 239
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`12.3 Data processing ............................................................................................ .. 242
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`12.4 Range of particle sizes and resolution ....................................................... .. 246
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`12.5 Experimental aspects
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`............................................................................ .. 246
`12.5.1 Sampling considerations
`12.5.2 Calibration
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`12.5.3 Reproducibility
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`12.5.4 Influence of measuring time and stirring speed ......................................... .. 248
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`12.6 Applications
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`12.6.1 Particle size measurement on highly concentrated o/w emulsions
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`12.6.2 Influence of formulation variables on the
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`size distribution of o/w emulsions
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`12.7 Conclusions
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`12.8 References
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`13 Large~scale production of liposomes by continuous high
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`pressure extrusion
`A. Sachse, Schering AG, Berlin
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`13.1 Introduction .................................................................................................. .. 257
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`13.2 Extrusion of liposome suspensions
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`13.3 Continuous high pressure extrusion .......................................................... .. 261
`13.4 Conclusions
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