3rd UKCRS Symposium on "Controlled Drug Delivery - Current Perspectives and Future Horizons" - Manchester 1997

Abstract Titles

Invited Talks

01 INTEGRATING MOLECULAR BIOSENSORS INTO LIPID BASED DELIVERY SYSTEMS TO ACHIEVE BIO-RESPONSIVE RELEASE
Prof. David Clarke
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK
02 UNDERSTANDING SURFACE MACROMOLECULAR INTERACTIONS IN THE DESIGN OF THERAPEUTIC SYSTEMS
Prof. Martyn Davies
University of Nottingham, UK
03 DESIGN OF NEW BIOMATERIALS FOR DRUG DELIVERY: TAILORING THE STRUCTURE TO SPECIFIC DELIVERY NEEDS AND RELEASE REQUIREMENTS
Nicholas A. Peppas
School of Chemical Engineering, Purdue University, West Lafayette, IN 47907-1283, USA
04 POLYMERIC MICROSPHERES FOR SUSTAINED DELIVERY OF THERAPEUTIC PROTEINS
Stephen E. Zale
Alkermes Inc., Cambridge MA, USA
05 PHARMACEUTICAL INFORMATION AND THE INTERNET
Antony D'Emanuele
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK
06 AN INDUSTRIAL PERSPECTIVE OF GENE THERAPY
Anthony J. Phillips
Glaxo Wellcome


Contributed Oral Presentations

01 BIODISTRIBUTION OF NOVEL PALMITOYL MURAMIC ACID 200nm VESICLES: LIVER AND SPLEEN UPTAKE
Ijeoma F. Uchegbu
Centre for Drug Delivery Research, School of Pharmacy, University of London, London
02 NOVEL BIODEGRADABLE POLYCAPROLACTONE COPOLYMER BLENDS
S. Berrill*, K. VirasÝ , J.P.A. Fairclough+ C Booth#, S .Browný , D. Attwood, J. Collett
Departments of Chemistry# and Pharmacy, University of Manchester; Department of
Chemistry, University of Athens+; Manchester Material Science Centre, UMIST+ ; Sanofi Winthrop, Alnwick Research Centreý
03 THE DIFFERENCE IN BIOLOGICAL PROPERTIES OF POLY(ETHYLENE OXIDE) COATED COLLOIDAL CARRIERS - RELATION TO THEIR PHYSICOCHEMICAL PROPERTIES
Stolnik, S., Garnett, M., Illum, L. Davis, S. S.
Department of Pharmaceutical Sciences, University of Nottingham


Poster Presentations

01 MORPHOLOGICAL STUDIES OF C6G2 NIOSOMES USING MICROSCOPY
P. Arunothayanum*, M.S. Bernard, D.McCarthy, I.F. Uchegbu, A.T. Florence
Centre for Drug Delivery Research, The School of Pharmacy, University of London
02 RHEOLOGICAL AND MORPHOLOGICAL STUDY OF POLYHEDRAL AND SPHERICAL/TUBULAR NIOSOMES
M.S. Bernard, P. Arunothayanun*, I.F. Uchegbu, A.T. Florence
Centre for Drug Delivery Research, The School of Pharmacy, University of London
03 POLYMER - NATURAL PRODUCT CONJUGATES AS ANTICANCER DRUGS
S. Dimitrijevic and R. Duncan
Centre for Polymer Therapeutics, The School of Pharmacy, 29-39 Broomstick Square, London WC1N 1AX, UK
04 EVALUATION OF POLYMER-MITOMYCIN C AND POLYMER-ALKLATING AGENTS AS POTENTIAL ANTICANCER AGENTS
Elisabetta Gianasi* and Ruth Duncan
Centre for Polymer Therapeutics, School of Pharmacy, 29/39 Brunswick Square, London
05 PAMAM DENDRIMERS FOR THE DELIVERY OF CISPLATIN
Navid Malik* and Ruth Duncan
Centre for Polymer Therapeutics, The School of Pharmacy, University of London 29-39 Brunswick Square, London WC1N 1AX
06 CONCURRENT ANALYSIS OF PERMEANT, ENHANCER AND SOLVENT INTERACTIONS: A MODEL FOR ASSESSING PENETRATION ENHANCEMENT
B.S. Grewal*, A.Naik, W.J. Irwin
Drug Delivery Research Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle Birmingham B4 7RT
07 COMPLEXATION OF BECOMETHASONE MONO AND DIPROPIONATES WITH CYCLODEXTRINS
G.M. Worth*, G. Taylor, S.J. Farr and M. Thomas1.
Welsh School of Pharmacy, University of Wales, Cardiff. CF1 3XF 1. Glaxo Wellcome, Park Road, Ware, Herts. SG12 ODP
08 INTRAGASTIC DISTRIBUTION AND RETENTION OF THE ANIONIC EXCHANGE RESIN, CHOLESTYRAMINE
S.J. Jackson*, N. Washington, D. Bush and R.J.C. Steele, Department of Surgery, University Hospital, Nottingham
09 STEREOSELECTIVE DRUG RELEASE FROM TRANSDERMAL ADHESIVES
C.J. Allender*, C.M. Heard & K. R. Brain
Welsh School of Pharmacy, UWC, Cardiff CF1 3XF
10 PROSPECTS FOR ENATIOSPECIFIC DRUG DELIVERY
C.M. Heard*, K.R. Brain and R. Suedee
Welsh School of Pharmacy, UWC, Cardiff CF1 3XF
11 DIFFUSIONAL PATHLENGTHS IN HYDRATED HUMAN STRATUM CORNEUM
M.A. Pellett1, A.C. Watkinson2, K.R. Brain1,2 and J. Hadgraft1
1The Welsh School of Pharmacy, UWCC, Cardiff, UK and 2An-Ex, Redwood Building, Cardiff, UK
12 CHARACTERISATION OF LIPID BASED GENE DELIVERY COMPLEXES
J.C. Birchall*, I.W. Kellaway, S.J. Farr and S. N. Mills1.
Welsh School of Pharmacy, University of Wales, Cardiff, CF1 3XF, UK 1Glaxo Wellcome, Park Road, Ware, Herts, SG12 ODP, UK
13 A STUDY ON THE MOLECULAR INTERACTIONS BETWEEN WATER AND CELLULOSE ETHER POLYMERS USING DSC
C.B. Crystal*, J.L. Ford and A.R. Rajabi-Siahboomi
Pharmaceutical Technology and Drug Delivery Group, School of Pharmacy and Chemistry, John Moores University, Byrom Street, Liverpool L3 3AF
14 EFFECT OF FABRICATION TECHNIQUE ON EROSION CHARACTERISTICS OF POLYANHYDRIDE DEVICES
H. Akbari*, A. D'Emanuele and D. Attwood
Department of Pharmacy, University of Manchester, Manchester M13 9PL UK
15 AMOXYLCILLIN RELEASE FROM A BUOYANT DOSAGE FORM
L. Whitehead*, J.T. Fell, J.H. Collett
Pharmacy Department, University of Manchester M13 9PL
16 THE RELEASE OF NORETHINDRONE FROM POLYHYDROXY BUTYRATE AND POLYHYDROXYVALERATE
H. Popli*, S.N. Sharma and J. Collett
Department of Pharmacy, University of Manchester, Manchester, UK
17 CELLULAR UPTAKE OF CHIMERIC HAMMERHEAD RIBOZYMES IN U87-MG GLIOMA CELLS
P. Fell*, M. Reynolds and S. Akhtar
Drug Development and Research Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham. B4 7ET
18 LIPOPHILIC ANTISENSE OLIGONUCLEOTIDE-CONJUGATES INTERFERE WITH THE ACTIVITY OF THE DIPEPTIDE TRANSPORTER SYSTEM IN CACO-2 CELLS
Vanessa A. Moore, Deborah J. Dunnion, William J. Irwin and Saghir Akhtar*
Laboratory of Molecular Therapeutics, Drug Delivery Group, Pharmaceutical Sciences Institute, Aston University, Birmingham. B4 7ET UK
19 THE EFFECT OF SURFACE PROPERTIES ON UPTAKE OF COLLOIDAL CARRIERS BY COMPONENTS OF THE RETICULO-ENDOTHELIAL SYSTEM, AS DETERMINED USING CONFOCAL LASER SCANNING MICROSCOPY
A. M. Hillery, R. Faragher, C. J. Olliff, A. W. Lloyd.
Department of Pharmacy, University of Brighton, Brighton BN2 4GJ
20 PREPARATION AND RELEASE OF IUDR AND 125IUDR FROM BIODEGRADABLE MICROSPHERES AND FILMS
Md. Selim Reza* and T.L. Whateley
Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow. G1 1XW
21 IS THE GEL STATE RESPONSIBLE FOR THE DEPOT EFFECT ACHIEVED BY VESICLE-IN-WATER-IN-OIL-EMULSIONS?
*Sudaxshina Murdan, Gregory Gregoriadis and Alexander T. Florence
Centre for Drug Delivery Research, School of Pharmacy, University of London, 29/39 Brunswick Square, London. WC1N 1AX UK
22 THE RELEASE CHARACTERISTICS OF ARA-C FROM A NOVEL HYDROGEL
M. Ameri*, D. Attwood, J.H. Collett and C. Booth1
Departments of Pharmacy and Chemistry1, University of Manchester, Manchester. M13 9PL UK
23 IN VIVO CHARACTERISATION OF PASSIVE AND IONTOPHORETIC PERCUTANEOUS ABSORPTION BY A.C. IMPEDANCE SPECTROSCOPY
G. P. Moss, A. D. Woolfson, D. F. McCafferty, E.T. McAdams, A. Lackermeier.
Queens's University, Belfast & Northern Ireland Bio-Engineering Centre, University of Ulster

Abstracts for Invited Talks

INTEGRATING MOLECULAR BIOSENSORS INTO LIPID BASED DELIVERY SYSTEMS TO ACHIEVE BIORESPONSIVE RELEASE
David J Clarke and Harmesh S Aojula
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PL, UK

Closed-loop, self-regulating delivery systems have been considered primarily using polymer systems responsive to physical and physiochemical triggers, providing a limited range of biologically specific (bioresponsive) controlled release systems. This has led to the consideration of diagnostic materials (eg concanavalin A and glucose oxidase for glucose, antibodies and streptavidin) to provide the biospecificities desired, using approaches (eg enzyme drive pH changes, coupled affinity reactions) reminiscent of first generation biosensors. Major efforts over the last two decades have been devoted to achieving intimate coupling between these biorecognition elements and the transducing device. However, few biosensor devices are yet considered reliable enough to be used in vivo as monitoring devices, or for feedback control (eg as may be used to close the loop on physically responsive polymer implants). Alternative non-invasive biosensor devices (eg near IR glucose monitoring) appear more promising, although they have a limited specificity range. Minimally invasive, miniaturised enzyme electrodes, microelectronic and optical immunobiosensors suffer from significant calibration drift and interference (non-specific reactions at the transducer surface). Like more recent molecular biosensor and heterogeneous molecular diagnostic methods, requiring multi-step assay procedures, they are directed largely to lab-based in vitro diagnostics, requiring expert or automated use.

Biology often uses biomembran es to couple biorecognition events or sensing to a variety of effector functions, closing the loop locally at the supermolecular of nanometre size scale. The integration of the biorecognition elements used in biology and in vitro diagnostics into biomembranes will be discussed, from the viewpoint of developing small, submicron-sized sample-going and targeted molecular biosensors for screening and bioresponsive controlled release systems. We will discuss work in our laboratory on the use of short biomimetic peptides to produce quantitative, bioresponsive release and transport of small molecules and proteins across biomembranes, and to bind reversibly to the variable and non-variable region of immunoglobulins.

UNDERSTANDING SURFACE MACROMOLECULAR INTERACTIONS IN THE DESIGN OF THERAPEUTIC SYSTEMS
Prof. Martyn Davies
University of Nottingham, UK

Surface interactions play a vital role in the performance of many advanced drug delivery systems. The adsorption of serum proteins to colloid surfaces plays a major role in determining their disposition in-vivo. The molecular recognition between the targeting groups on soluble polymeric delivery systems and the cell surface receptors is another example of the importance of surface interactions. In order to provide a greater understanding of these interfacial properties, one may exploit a number of advanced biophysical techniques which have been developed to define surface phenomena. This talk will explore the role of two developing methodologies which show considerable promise for the study of biomolecular structure and interactions with advanced biomaterials: atomic force microscopy (AFM) and surface plasmon resonance (SPR). AFM can provide high resolution imaging of biomolecular and polymer structure of relevance to controlled drug delivery within an aqueous environment. Dynamic events such as surface hydration, degradation and biomolecular interactions can be visualised in situ. Important surface properties such as compliance, friction and force of interactions between biomolecules can all be probed. SPR is emerging as one of the most important tools for studying biomolecular structure and interactions. This talk will describe how the technique may be adapted to provide kinetic information on the dynamic events at interfaces including DNA-protein interactions of importance in gene therapy, macromolecular interactions at membrane interfaces and protein interactions at nanoengineered surfaces designed for site-specific delivery and diagnostic applications. The talk will illustrate the complimentarity of these two approaches, alongside other biophysical, biochemical and in-vivo data, in gaining a greater insight into understanding the performance of advanced delivery systems, in certain cases, at the molecular level.

DESIGN OF NEW BIOMATERIALS FOR DRUG DELIVERY: TAILORING THE STRUCTURE TO SPECIFIC DELIVERY NEEDS AND RELEASE REQUIREMENTS
Nicholas A. Peppas
School of Chemical Engineering, Purdue University, West Lafayette, IN 47907-1283, USA

Recent developments in polymeric materials have played a major role in improving drug delivery. Drugs, peptides or proteins are now chemically attached to polymers or antibodies, entrapped in small vesicles that are injected into the blood, or placed in pumps or controlled release devices in contract with the body. Recent developments in drug delivery have been directed towards the preparation of targeted formulations for peptide delivery to specific sites, use or environmentally-responsive polymers to achieve pH- or temperature-triggered delivery, usually in modulated mode, and improvement of the behaviour of mucoadhesive controlled release systems. Renewed interest is directed towards the study to antibody-directed enzyme prodrug therapy, tumor suppressor gene therapy for cancer, novel methods of delivery of insulin, calcitonin, growth hormones and vaccines.

Intelligent biomaterials can be used for a wider range of biomedical applications such as membranes for bioseparations, carriers for pH- or temperature-triggered drug delivery, materials in immunologic studies, and systems for feedback-control devices. We show that the critical behaviour of such polymers lead to abrupt expansion (swelling)/collapse (syneresis) of their structure with associated change to the mesh size or correlation length. These phenomena can be used for the release of insulin, vitamins, etc. in an oscillatory mode. Success of such systems will depend on our ability to show that the observed behaviour is reproducible over several thousand cycles without polymer failure, and that external physiological changes have minor influence on the release behaviour.

POLYMERIC MICROSPHERES FOR SUSTAINED DELIVERY OF THERAPEUTIC PROTEINS
Stephen E. Zale Alkermes, Inc.,
Cambridge MA, USA

Therapeutic proteins are generally administed by frequent injection because of their characteristic negligible oral bioavailability and short plasma half life. Potential benefits of injectable microsphere-based sustained release delivery systems for protein drugs include improved patient compliance and convenience, more stable blood levels and a possible reduction in the dose required to achieve a therapeutic effect. The controlled release of protein drugs is a serious challenge, however, because the fragile nature and complexity of protein molecules. Protein stability towards the encapsulation process, during product storage and during in vivo release are critical issues that must be confronted in order to develop a sustained release system for a therapeutic protein. Process and formulation strategies addressing the issue of protein integrity and stability in injectable, biodegradable polymeric microsphere products will be discussed.

PHARMACEUTICAL INFORMATION AND THE INTERNET
Antony D'Emanuele
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.

The concept of a global computer network originated in the 1970s, however, prior to the 1990s, the Internet was in a relatively dormant state and the primary users were the academic community. The surge of interest in the Internet can be traced to the development of the World Wide Web (WWW) and the user-friendly interface it presents. The Internet is evolving into a powerful and global resource for communications and information retrieval. Despite major developments, the Internet is still in an embryonic state and there are several important issues to be addressed if it is to realise its potential. The main issues in the foreseeable future are bandwidth, hardware requirements, security and indexing of information. Provided these issues are addressed, the Internet promises to revolutionise the way we communicate and exchange information. Indeed, the Internet is probably the most important development in communications since the telephone.

Information retrieval and communication are two important aspects of the work of pharmacists and pharmaceutical scientists and the Internet is an ideal medium by which these activities can be facilitated. PharmWeb has been developed as an information resource on the Internet for medicine, pharmacy and health-related professions. PharmWeb has been designed to be interactive and encourages the exchange of information via a range of technologies including on-line discussion groups. PharmWeb is mirrored in several countries around the world and has been accessed by over 110 countries. Current access of the UK servers alone is at a rate of approximately 140,000 page requests per month (November 1996).

A review of current developments on the Internet will be presented together with the pharmaceutical applications of Internet technology.

AN INDUSTRIAL PERSPECTIVE OF GENE THERAPY
Anthony J. Phillips
Glaxo Wellcome

There have been over 4,000 diseases that have been identified as being caused by defects in genes. In addition, there are acquired diseases, eg AIDS, that are potential targets.

Gene therapy offers the potential to cure or greatly reduce the symptoms of a broad range of disease including:

- Gene-related disorders such as severe combined immune deficiency (SCID)

- Heredity-related disorders such as familial hypercholesterolaemia and cystic fibrosis.

- Viral-related diseases such as AIDS.

- Diseases such as cancer where there is a combination of causes.

The potential to develop better treatments for a wide range of diseases has created the enormous interest in gene therapy. The possible market is very large if the technical and market challenges can be met. Challenges for the successful commercialisation of gene therapy include:

- Systemic vs local delivery.

- Safety issues, particularly when viral vectors are used.

- Efficacy and duration of achievable therapy.

Until comparatively recently, the technology was largely confined to academia and specialist Biotech companies. The large pharmaceutical companies have entered the field by strategic alliances with potential utilisation in CF, oncology and HIV. The development of such products is very different from that of conventional drugs but more closely associated with biologicals. Even then there are differences in approach to production of the DNA vector system, its characterisation and the evaluation of safety.

The issues that face development of these products are as follows:

- Targeting to the cells of interest.

- Transfection with subsequent expression of the desired protein.

- Manufacture at the scale required.

- Demonstration of safety to the satisfaction of the Regulatory Authorities.

The presentation will explore these issues using examples of viral and non-viral based systems.


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