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GAZETTE
9th World Meeting on Pharmaceutics and Biopharmaceutics
March 31-April 3, 2014 Lisbon, Portugal
See page 5
7th PSSRC Symposium “Open day” July 5, 2013 Lille, France
See page 3
2012
N°28 Issue 1
www.apgi.org
3rd Conference on Innovation in Drug Delivery
September 22-25, 2013 Pisa, Italy
See page 4
See page 2
2nd APGI COATING WORKSHOP University of Lille, Lille, France
April 17, 2013
"The Place for Innovation in Film Coating"
Invited speakers
Prof. A. Basit, University of London, UK
Prof. R. Bodmeier, University of Berlin, Germany
Prof. A. Gazzaniga, University of Milan, Italy
Prof. T. Rades, University of Copenhagen, Denmark
Prof. J. Siepmann, University of Lille, Lille, France
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CONTENT
Editorial 1 International News 2 2nd APGI Coating workshop 2 7th PSSRC Symposium 3 3rd Conference on Innovation in Drug Delivery 4 9th PBP World Meeting 5 Information day “Drying process for industry” 6 Skin & Formulation 4th Symposium 7 9th CESPT 12 Information day Controlled drug & flavour release 13 Interreg IDEA 15 New Technologies 16 Mass spectrometry imaging in pharmaceutics 16 Colloidal carriers for dermal delivery 21 Agenda 26
XXXXXXXXXXXXXXXXXXXXXXXXXXX Call for APGI Thesis Award 2011/2012
This annual price, granted jointly by SANOFI R&D and APGI, recognize thesis written as the
culmination of the pharmaceutical technology PhD programme.
If you have defended your PhD thesis in 2011/2012, you can apply for the APGI thesis award
2011/2012. The amount of the Prize is 1500 € .
To apply, please send, by 31th January, 2013, three copies of your thesis manuscript (hard
copy only) and a short curriculum vitae to the APGI secretariat: :
5 rue Jean-Baptiste Clément,
FR-92296 Châtenay-Malabry, Cedex, France.
APGI board Président : Pr. Juergen Siepmann Vice-Président : Dr. Vincent Jannin Trésorière : Pr. Marie-Pierre Flament Secrétaire : Pr. Odile Chambin Membre : Dr. Maria Teresa Peracchia Membre : Dr. Régis Cazes Membre : Dr. Karine Andrieux
APGI council Dr. Karine Andrieux Pr. Philippe Arnaud Dr. Emeline Berlier Dr. Amélie Bochot Dr. Kawthar Bouchemal Dr. Sandrine Bourgeois Dr. Régis Cazes Pr. Renée de Challemaison Pr. Odile Chambin Dr. Caroline Chemin Dr. Michel Deleers Pr. Elias Fattal Pr. Marie-Pierre Flament Dr. Alexandre Gil Dr. Vincent Jannin Dr. Youness Karrout Dr. Caroline Lemarchand Dr. Maria Teresa Peracchia Dr. Géraldine Piel Pr. Véronique Préat Dr. Christel Raffournier Dr. Florence Siepmann Pr. Juergen Siepmann Pr. Pascal Wehrlé
Benefactory member
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Editorial 1 International News 2 2nd APGI Coating workshop 2 7th PSSRC Symposium 3 3rd Conference on Innovation in Drug Delivery 4 9th PBP World Meeting 5 Information day “Drying process for industry” 6 Skin & Formulation 4th Symposium 7 9th CESPT 12 Information day Controlled drug & flavour release 13 Interreg IDEA 15 New Technologies 16 Mass spectrometry imaging in pharmaceutics 16 Colloidal carriers for dermal delivery 21 Agenda 26
Dear Colleagues
The 4th Symposium "Skin & Formulation” held in Lyon on 4-5 June 2012 was a great success:
More than 100 abstracts were presented as posters or oral communications, and more than 240
scientists from all over the world participated at this outstanding event. For the first time the
symposium was jointly organized together with the European Centre of Dermocosmetology
(CED), which proved to be a highly fruitful cooperation.
The major up-coming international events include:
The 2nd APGI Coating Workshop, which will be held in Lille, on 17 April 2013. As the first workshop of this kind, it will be
an interesting mix of invited oral presentations from academia and industry, an industrial exhibition and practical
demonstrations. The entire spectrum, ranging from: engineering aspects during the coating process, the portfolio of
commercially available coating polymers, the underlying drug release mechanisms, characterization methods for thin
film coatings, drug release measurement techniques as well as potential pitfalls and hurdles to be overcome during
product development will be addressed.
The “Open Day” of the 7th Annual PSSRC (Pharmaceutical Solid State Research Cluster) Symposium, which will be orga-
nized on 5 July 2013 in Lille. The particular focus of this meeting will be on Advanced Characterization Techniques for
Solid Pharmaceutical Dosage Forms. Internationally highly recognized invited speakers will give overviews on the cur-
rent state of the art on topics, such as the characterization of different forms of amorphous solids, methods to deter-
mine drug solubility in polymeric carriers, scanning white light interferometry, hyperspectral imaging, low frequency
Raman micro-spectroscopy, MRI characterization of solid pharmaceutical dosage forms, terahertz pulsed spectroscopy
and imaging, to mention just a few.
The 3rd Conference on Innovation in Drug Delivery, which will be organized together with our Italian friends (the
ADRITELF) on 22-25 September 2013 in Pisa. Following the great success of the two first symposia of this kind in Naples
and Aix-en-Provence, the conference will allow for a fruitful exchange between academia and industry. The specific “hot
topic” selected for 2013 will be "Advances in Local Drug Delivery".
The 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, which will be jointly
organized with the APV, ADRITELF and many other societies in Lisbon on 31 March to 3 April 2014. This conference has
gained an ever increasing impact among the pharmaceutical scientists, with close to 1000 submitted abstracts and 1500
expected participants. It has become the biggest meeting in Pharmaceutics in Europe.
In addition, we will be very happy to welcome you at one of our upcoming information days, such as the one held in
Castres on 5 April 2013, focusing on "Drying Process for Industry".
We wish you a very successful and interesting New Year!
Juergen Siepmann
President of APGI
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EditorialEditorialEditorial
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International NewsInternational NewsInternational News
2nd APGI Coating Workshop April 17, 2013, University of Lille, Lille, France
Following the great success of the 1st
APGI Coating Workshop held in 2008
in Lille, the APGI will organize for the
second time a workshop dedicated to
the coating of solid dosage forms.
During the one day event, oral and poster presentations from
academia and industry as well as practical demonstrations (in
small groups) are foreseen. The entire spectrum, ranging from:
engineering aspects during the coating process, the portfolio
of commercially available coating polymers, the underlying
drug release mechanisms, characterization methods for thin
film coatings, drug release measurement techniques as well as
potential pitfalls and hurdles to be overcome during product
development will be addressed.
Outstanding scientists from all over the world will give invited
plenary lectures in the field, this includes:
Furthermore, 6 practical demonstration sessions (20 min
each, in 6 groups of 25 participants) will encompass:
Coating equipment: GEA, Glatt, ProCept
Compression coating: Medelpharm
Dissolution testing: Sotax
Advanced characterization: Malvern.
The industrial exhibition will give an update on the current
state of the art of technical developments in the field and en-
compasses:
BASF, Biogrund, Caleva Process Solutions Ltd., Evonik Pharma
Polymers, Gamlen Tableting Ltd., Glatt GmbH, IMA France,
Kerry, Lödige, Merck Millipore, ProCepT, Roquette, Shin-Etsu,
Sotax, Stern Maid GmbH.
The sponsors of the meeting are:
Platinum sponsors
Silver sponsors
In case your company is interested to join the exhibition (the
number of remaining booths has become very limited) or to
act as a sponsor for the meeting, please contact:
The workshop will be held at the
University of Lille, College of Pharma-
cy, 3 Rue du Professeur Laguesse,
59006 Lille, France. Lille is a very live-
ly city in Northern France and can be
easily reached by train (TGV and Eu-
rostar: 30 min from Brussels, 1 h from
Paris, 1.2 h from London), by plane
(Lille Lesquin Airport or Paris Charles
de Gaulle Airport – 50 min by train)
as well as by car.
As practical demonstrations are included, the maximum num-
ber of participants is limited to 150.
Details on accommodation, registration fees, important dead-
lines and sponsoring possibilities are available on our website:
http://www.apgi.org/coating_WS.
Prof. T. Rades, University of Copenhagen, Denmark
Advanced characterization of film coatings
Prof. A. Gazzaniga, University of Milan, Italy
Film coatings for oral colon targeting
Prof. A. Basit, University of London, UK
Importance of food effects for controlled release film
coatings
Prof. J. Siepmann, University of Lille, France
Stability of aqueous controlled release film coatings
Prof. R. Bodmeier, University of Berlin, Germany
Compression coating and compression of coated pellets
T. Cech, BASF, Germany
Scaling-up of pan coating processes
Dr. R. Chokshi, FMC Biopolymer, USA
Title to be announced
Dr. V. Jannin, Gattefossé, France
Hot-melt coating with lipid excipients
Dr. A. Rajabi-Siahboomi, Colorcon, USA
HPMC- and PVA-based film coatings
Dr. J. Albers, Evonik, Germany
QBD case study: Optimization of process parameters for an
extended release particle coating with Eudragit® NM 30 D
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International NewsInternational NewsInternational News
2nd APGI Coating Workshop April 17, 2013, University of Lille, Lille, France
7th Annual PSSRC Symposium “Open Day” July 5, 2013, University of Lille, Lille, France
The Pharmaceutical Solid State Research Cluster (PSSRC, www.pssrc.org) counts 11 academic laboratories, located at the Universities of Cambridge (United Kingdom), Copenhagen (Denmark), Duesseldorf (Germany), Ghent (Belgium), Graz (Austria), Helsinki (Finland), Leuven (Belgium), Lille (France), Lisbon (Portugal), Ljubljana (Slovenia) and Otago (New Zea-land).
The aim of this consortium is to overcome current limitations in the formulation of solid pharmaceutical dosage forms: Novel systems and strategies are developed, ensuring the quality of medicines.
Every year, the PSSRC organizes its Annual Meeting at one of the partner’s locations. These meetings are dedicated to the next generation of pharmaceutical scientists (doctoral students and post-docs). The 3 days events give the Young Scientists the unique opportunity to network and share professional expe-riences: They present posters and lectures and discuss their latest research findings.
One of the 3 days is the “Open PSSRC Day”, during which inter-nationally highly recognized experts in the field present over-views on the current state of the art of “hot topics”. Next year the focus will be on Advanced Characterization Methods for Solid Pharmaceutical Dosage Forms.
Speakers will address the characterization of different forms of amorphous solids, analysis of solid dispersions with thermoana-lytical techniques, methods to determine drug solubility in po-lymeric carriers, scanning white light interferometry, hypers-pectral imaging, low frequency Raman micro-spectroscopy, MRI characterization of solid pharmaceutical dosage forms, X-ray tomography, terahertz pulsed spectroscopy and imaging, NIR spectroscopy, recent advances in Process Analytical Technology (PAT), more realistic models studying the fate of lipids in the gastro intestinal tract, taste masking and the elucidation of drug release mechanisms.
In addition to these invited talks given by leading researchers in field, poster presentations by Young Scientists on recent research findings will allow getting an update on the most ad-vanced characterization techniques available nowadays.
The “Open PSSRC Day” will be held at the College of Pharmacy, University of Lille, France, on Friday 5 July 2013 and will include the following invited lectures:
In addition, an industrial exhibition will allow getting an update on the most recent technical development in the field of Advan-ced Characterization of Solid Pharmaceutical Dosage Forms.
In case your company is interested to join the exhibition or to
act as a sponsor for the meeting, please contact: [email protected]
For more information, please
visit the meeting’s website:
http://www.apgi.org/pssrc_2013
Advanced Characterization Techniques for Solid Pharmaceutical Dosage Forms
OPEN DAY SCIENTIFIC PROGRAMME
Prof. Thomas Rades, University of Copenhagen, Denmark Characterization of different forms of amorphous solids
Prof. Guy van den Mooter, University of Leuven Analysis of solid dispersions with thermoanalytical techniques
Prof. Marc Descamp, University of Lille 1, France How to determine drug solubility in a polymeric carrier?
Prof. Niiklas Sandler, Åbo Akademi University, Finland
Scanning white light interferometry (SWLI)
Dr. Clare Strachan, University of Helsinki, Finland Hyperspectral imaging
Dr. Mick Mantle, University of Cambridge, UK MRI characterization of solid pharmaceutical dosage forms
Prof. Alain Hedoux, University of Lille, France Solid state transformations of APIs induced by manufacturing processes analyzed by micro-Raman spectroscopy
Dr. Axel Zeitler, University of Cambridge, UK X-ray tomography and Terahertz pulsed spectroscopy and ima-ging
Prof. Jukka Rantanen, University of Copenhagen, Denmark The potential of NIR spectroscopy: Insight into solid state transformations during processing
Prof. Thomas De Beer, University of Ghent, Belgium What is new in PAT (Process Analytical Technology)?
Prof. José C. Menezes, University of Lisbon, Portugal Quality by Design in fluid bed granulation
Prof. Anette Muellertz, University of Copenhagen, Denmark Towards more realistic models studying the fate of lipids in the GIT
Prof. Joerg Breitkreutz, University of Duesseldorf, Germany How to evaluate taste masking?
Prof. Juergen Siepmann, University of Lille 2, France How can drug release mechanisms be elucidated?
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After the considerable suc-
cess of the first two Confe-
rences on "Innovation in
Drug Delivery" in Naples
(2007) and Aix en Provence
(2010), the ADRITELF and
APGI will be jointly organizing third appointment of the series:
The next meeting will be held in Pisa on 22 - 25 September
2013 and mainly focus on “Advances in Local Drug Delivery”.
This is a highly challenging topic for the development of new
therapeutic approaches. About 350 to 400 participants are
expected (350 attendees came to Naples).
The conference will cover a large range of topics related to
Local Drug Delivery, including: drug targeting, topical adminis-
tration, in situ forming systems as well as biomaterials. This
important event will represent a stimulating occasion capable
to foster intellectual and scientific exchanges among the parti-
cipants. As in the past, plenary and invited lectures as well as
oral and poster contributions will be presented.
In addition, an industrial exhibition will allow getting familiar
with the latest technical developments in the field of Local
Drug Delivery. If your company is interested to act as a spon-
sor and/or exhibitor, please contact: [email protected].
Your contribution will help intensifying the fruitful exchange
between academia and industry and at the same time pro-
mote the awareness of your activities in the pharmaceutical
field.
The scientific programme includes outstanding presentations
from world-wide recognized experts in the field.
The invited plenary lectures will be given by:
Invited lectures will be presented by:
Dr. Amélie BOCHOT, University of Paris-Sud, France
Nano and Microparticulate Systems for Ophthalmic
Drug Delivery
Prof. Patrizia CHETONI, University of Pisa, Italy
Nail Drug Delivery: Challenges and Advances
Prof. Paolo COLOMBO, University of Parma, Italy
Particles, Powders and Inhalation Products
Prof. Elias FATTAL, University of Paris-Sud, France
Nanotechnologies Targeting the CD 44 Receptor
Prof. Andrea GAZZANIGA, University of Milan, Italy
Formulation Approaches to Colon Delivery: an Overview
Prof. Claus Selch LARSEN, University of Copenhagen,
Denmark
Depot Injectables for Joint Instillation
Prof. Jean-Christophe LEROUX, ETH, Zurich, Switzerland
Presystemic Interventions for the Treatment of Celiac Disease
Dr. Claudia MONTERO-MENEI, INSERM Angers, France
Drug and Cell Delivery to the Brain
Prof. Alec N. SALT, Washington University School of
Medicine, St. Louis, Missouri, U.S.A.
Technical Challenges in Local Delivery of Drugs to the Inner Ear
Prof. Gert STORM, University of Utrecht, The Netherlands
Application of High Intensity Focused Ultrasound (HIFU) for
Tumor-Targeted Temperature-Responsive Drug Delivery
Prof. Elka TOUITOU, Hebrew University of Jerusalem, Israel
Nasal Delivery of Drugs for Efficient CNS Diseases Treatment
3rd Conference on “Innovation in Drug Delivery” September 22-25, 2013, Congress Center of Pisa, Pisa, Italy
Advances in Local Drug Delivery
Prof. Fabio BELTRAM, NEST Laboratory, Scuola Normale Superiore, Pisa, Italy
Nanotechnology, How It Can Help
Prof. Gregor CEVC, Advanced Treatments Institute, Gauting, Germany
Colloid Formulation Effects on (Trans)Dermal Drug Delivery
Prof. Justin HANES, Johns Hopkins University, Baltimore, Maryland, U.S.A.
Mucus Penetrating Nanoparticles for Pulmonary Drug and Gene Delivery
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International NewsInternational NewsInternational News
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In continuation of the very
successful past scientific mee-
tings in Budapest, Paris, Berlin,
Florence, Geneva, Barcelona,
Malta and Istanbul, the 9th
World Meeting on Pharma-
ceutics, Biopharmaceutics and
Pharmaceutical Technology will be held in Lisbon on 31st
March to 3rd April 2014.
This conference has gained an ever increasing impact among
the pharmaceutical scientists, with close to 1000 submitted
abstracts and 1500 expected participants. It has become the
biggest meeting in Pharmaceutics in Europe.
In 2014, special emphasis will be placed on industrial related
topics. Two of the four parallel oral sessions will focus on the
following hot topics:
• Pharmaceutical manufacturing & engineering
• Pharmaceutical excipients
• Nanomaterials & nanotechnologies
• Green & sustainable Pharma
• Personalized medicines & Theragnostics
• Patient-centred drug delivery, Pediatrics & Geriatrics
• Veterinary medicines
• Advanced therapy medicinal products
• Protein formulation and aggregation
• Biopharmaceuticals & Biosimilars
• Advances in controlled drug delivery
• Poorly soluble drugs
• Advanced analytics & Process analytical technologies
• Outsourcing strategies
• Drug counterfeiting
• Generics & NBCDs
The APGI, A.D.R.I.T.E.L.F. and APV invite you to discuss the
risks, opportunities and challenges of the development and
production of new medicinal products and medical devices. In
addition to the two parallel sessions on industry-related topics
presented by distinguished invited speakers, the 9th World
Meeting, like its recent predecessors, will have two more pa-
rallel tracks which provide ample room for a number of oral
presentations given by young or established scientists from all
over the world. In these contributions selected from many
hundreds submitted abstracts by the Programme committee,
most recent scientific findings and experiences will be pre-
sented on a broad range of topics related to Pharmaceutics,
Biopharmaceutics and Pharmaceutical Technology.
Along with the poster presentations of the submitted papers
the exhibition ResearchPharm® will take place presenting the
newest trends and novel products in the area of pharmaceuti-
cal ingredients, developing and processing equipment, analyti-
cal technologies, medicinal products, medical devices, contract
manufacturing and recent publications.
In case your company is interested to join the exhibition or to
act as a sponsor for the meeting, please contact: apgi.asso@u-
psud.fr
The meeting is intended to bring together people working in
fundamental and applied academic research, chemical and
pharmaceutical industry and the regulatory field offering the
opportunity to initiate fruitful discussions and collaborations.
Furthermore, the programme of the conference will include
technical sessions devoted to specific scientific equipment,
techniques or other tools in the fields related to the topic
“Advances in Local Drug Delivery”. If you are interested in
giving a lecture (20 min) in the technical session of the confe-
rence, please contact: [email protected] or
Contributed papers will be presented from 23 to 25 Septem-
ber, 2013, either orally or in poster form. Abstracts of contri-
buted papers and submission forms must be sent by e-mail by
the corresponding author to APGI ([email protected]) by 1
March, 2013. For the presentation of abstracts, the authors
must carefully follow the sample that can be downloaded from
the website, which will be available soon.
For more details, please visit the APGI’s website at :
http://www.apgi.org
9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology March 30-April 3, 2014, Lisbon, Portugal
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COMITE D’ORGANISATION Dr. Kawthar Bouchemal - Maitre de Conférences HDR, Institut Galien Paris Sud, UMR CNRS 8612, Université Paris Sud
M. Mostafa Nakach - SANOFI R&D
Dr. Maria-Teresa Peracchia - SANOFI R&D
Dr. Maria-Inês Ré - Centre RAPSODEE CNRS UMR5302, Ecole des Mines d'Albi Carmaux
PROGRAMME (*La pause café et le déjeuner sont compris dans l’inscription) 9h00 – 9h20 : Arrivée des participants autour d’un café.
9h20 – 9h30 Mot de Bienvenue du Président de Castres-Mazamet Technopole(CEEI) et Vice-président de la Communauté d'agglomération de Castres – Mazamet. M. Philippe Leroux.
9h30 – 10h00 : - Présentation de l’école des mines d’Albi. Dr. René David – Ecole des Mines d’Albi.
- Présentation de l’APGI. Dr. Kawthar Bouchemal - Institut Galien Paris Sud, UMR CNRS 8612 - Université Paris Sud.
- Présentation de la société SANOFI. M. Mostafa Nakach – Sanofi R&D.
10h00 – 10h30 : Rappels des fondamentaux du séchage et différents modes de séchage en milieu industriel.
M. Jean-René Authelin - Sanofi R&D.
10h30 – 11h00 : Pause café*
11h00 – 11h30 : Utilisation optimale de l’énergie dans les procédés de séchage. Dr. Patricia Arlabosse – Ecole des Mines d’Albi.
11h30 – 12h00 : Développement d’une forme lyophilisée injectable et transposition industrielle. Dr. Bertrand Woinet - Sanofi R&D.
12h00 – 13h30 : Déjeuner*
13h30 – 14h40 : Visite de La Plateforme Technologique en Galénique Avancée – GALA.
14h40 – 15h20 : Etude de cas 1 : Séchage par atomisation. M. Jean-René Authelin - Sanofi R&D / M. Filipe Gaspar – HOVIONE
15h20 – 15h40 : Etude de cas 2 : Séchage des microparticules en utilisant le spray-drying.
Dr. Nicolas Tsapis – Institut Galien Paris Sud, UMR CNRS 8612 – Université Paris Sud.
15h40 – 16h20 : Etude de cas 3 : Le séchage en lit d'air fluidisé en aval d'un procédé de granulation.
Partie 1 (15h40 - 16h00) Séchage en lit d’air fluidisé après granulation humide.
Dr. Cécile Gabaud-Renou - Sanofi R&D.
Partie 2 (16h00 - 16h20) Couplage compoundeur - granulateur continu et séchage en lit d'air fluidisé :
efficacité pour l'industrie pharmaceutique. M. Florent Jego - ThermoFisher.
16h20 – 16h40 : Etude de cas 4 : Séchage conductif. M. Mostafa Nakach - Sanofi R&D.
16h40 - 17h00 : Questions - Clôture de la journée
COMMENT S'INSCRIRE ?
Vous êtes déjà membre de l'APGI et vous souhaitez participer à cette journée d'information, vous devez alors renouveler votre
adhésion à l’APGI pour l’année 2013. Pour cela il suffit de vous inscrire en ligne : http://apgi.org/frform1.htm et de préciser votre souhait de participer à la journée d'infor-mation en cochant la case Journée d’information APGI – Sanofi-Aventis.
Vous n’êtes pas encore membre et vous souhaitez participer à cette journée ainsi qu’aux prochaines journées d’information
organisées par l’APGI durant l’année 2013. Pour cela, veuillez compléter le formulaire d'adhésion à l'APGI en ligne pour 2013 : http://apgi.org/frform1.htm
SPONSORING /EXPOSITION /PRESENTATION POSTERS : www.apgi.org – E-mail : [email protected]
Information day APGI – SANOFI Le séchage en milieu industriel April 5, 2013, Espace Ressources - Le Causse Espace d'Entreprises, Castres
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Information day APGI – SANOFI Le séchage en milieu industriel April 5, 2013, Espace Ressources - Le Causse Espace d'Entreprises, Castres
Les 4 et 5 juin derniers l’AGPI et le Centre Européen de Dermo-
cosmétologie (CED) unissaient leurs forces pour accueillir le
4ème symposium Skin & Formulation au Palais des congrès de
Lyon. Trois-cents congressistes ont ainsi assisté à ces deux
journées mêlant un public international issu de l’industrie
cosmétique et du monde académique. Une fabuleuse soirée
de gala organisée par la société Gattefossé dans la salle de la
corbeille de la Chambre de Commerce et de l’Industrie de Lyon
a constitué le point d’orgue de ces deux journées.
Les conférenciers invités ont répondu présent, et de jeunes
chercheurs ont pu présenter leurs travaux lors de short confé-
rences. Des posters exposés dans des espaces conviviaux ont
donné lieu à des échanges durant les pauses et le prix APGI du
meilleur poster a été attribué à Mirjam Gosenca de l’Université
de Ljubljana à l’issue du symposium.
Le programme comprenait des sessions axées sur la biologie
cutanée et les nouvelles méthodes d’études de la peau ainsi
que des sessions axées sur la formulation avec notamment
cette année une nouveauté : le maquillage et la formulation
des poudres.
Après un accueil des participants par le Professeur François-
Noël Gilly, Président de l’Université Claude Bernard Lyon1, le
Docteur Dominique Bouvier, Présidente du CED et le Profes-
seur Jurgen Siepmann, Président de l’APGI, le congrès a débu-
té par l’étude de la barrière cutanée avec le Professeur Joke
Bouwstra (Université de Leiden) qui a axé sa présentation sur
la fonction barrière des patients atopiques. Sa conférence a
porté sur l’implication des lipides épidermiques dans cette
pathologie. Le professeur Bouwstra a montré l’impact de l’or-
ganisation des lipides et de la longueur des chaînes de diffé-
rentes céramides sur la perte insensible en eau et le NMF.
Si le rôle des lipides épidermiques est très important dans
l’intégrité de la fonction barrière, il est considérablement ren-
forcé par la présence des jonctions serrées (JS) (tight junctions)
ainsi que nous l’a rappelé le Docteur Marek Haftek (Université
Claude Bernard Lyon1). Dans sa présentation le rôle clé des JS
sur la compartimentalisation de l’épiderme a été expliqué avec
le contrôle de la polarisation des cellules qui permet par
exemple le déversement des corps d’Odland uniquement à
l’apex des kératinocytes. Il a, en outre, montré leur rôle déter-
minant dans le processus de différenciation des kératinocytes,
la cohésion du SC et sa desquamation. La régulation des jonc-
tions serrées a un rôle important dans la perméabilité cutanée.
La détection des perturbations de l’organisation et de la com-
pacité des lipides épidermiques peut être suivie par des mé-
thodes spectroscopiques puissantes telles que la microscopie
confocale Raman et la spectroscopie infrarouge, comme nous
l’a expliqué le Professeur Arlette Baillet (Université Paris Sud).
Dans sa conférence, elle nous a montré à l’aide de trois
exemples successifs l’intérêt de ses méthodes non invasives
pour détecter les différences dans la composition des lipides
du film hydrolipidique de surface en fonction de la région géo-
graphique et des habitudes alimentaires, l’hyperplasie épider-
mique qui survient après irradiation aux UVB et, enfin les mo-
difications qui surviennent avec l’âge. Cette compréhension du
tissu natif est également étudiée in vitro grâce aux progrès de
l’ingénierie tissulaire et aux modèles qui se construisent pour
évaluer les produits comme nous l’a exposé le Dr Thomas Fors-
ter (directeur de la recherche de Henkel) :
(1) des modèles au service de la toxicologie pour évaluer les
produits et assurer la sécurité des consommateurs avec
les hémi-cornées reconstruites et les épidermes recons-
truits afin de remplacer par des méthodes non invasives
le fameux test de Draize ;
(2) des modèles au service de la recherche avec l’analyse
fonctionnelle des gènes, du métabolisme cutané et de
l’efficacité. La recherche avance avec bientôt un cuir che-
velu reconstruit : un follicule pileux dans un milieu de
culture, une prouesse technologique !
Le Docteur Alexa Patzelt (Université de Berlin), nous a exposé
les enjeux du passage trans-folliculaire caractérisé par un effet
réservoir très important. En fonction de la taille des objets
susceptibles d’entrer dans le follicule comme des particules
polymériques, il est possible de moduler le passage et de cibler
Skin & Formulation 4th Symposium June 4-5, 2012, Lyon Congress Centre, Lyon, France
Gala organisé par la société Gattefossé à la Chambre de Commerce et de l’Industrie de Lyon
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une région : l’infundibulum, le bulge ou la papille. Elle nous a
aussi présenté des méthodes permettant de discriminer le
passage épidermique du passage trans-folliculaire. La peau est
un organe sensible à l’environnement et tester le devenir
d’une substance appliquée sur la peau est un processus long et
minutieux pour obtenir des résultats significatifs. Le Docteur
Thierry Oddos (directeur développement technologique des
Laboratoires Johnson & Johnson Santé Beauté France) nous a
présenté les changements majeurs dans l’expression des gènes
cutanés suite à l’application de nombreuses substances et
même en fonction de l’humidité relative de l’air. Outre les
caractéristiques physicochimiques des molécules entrantes,
pour s’affranchir de nombreux facteurs dont celui de l’humidi-
té relative de l’air, le Professeur Philippe Humbert (Université
de Franche Comté) nous a présenté un nouveau modèle de
cellules de Franz breveté, régulé en température et en humidi-
té relative ainsi que des kits prêts à l’emploi avec des peaux
entières validées et préparées pour la pénétration cutanée. Au
cours de sa présentation étayée par de nombreux exemples,
nous avons suivi les cinétiques de passage de substances telles
que la caféine ou le VX (toxique de guerre) dans ce nouveau
dispositif en fonction de ces paramètres et observé les diffé-
rences de flux qui s’opèrent. Le Professeur Jim Rivière
(Université de Caroline du Nord) nous a rappelé les enjeux de
la pénétration cutanée et combien prédire le passage des
substances est compliqué avec une nouvelle lecture de l’équa-
tion de Potts and Guy. La deuxième journée s’est concentrée
sur la galénique et les nouvelles formes topiques. Les émul-
sions sont les formes galéniques phares en dermopharmacie et
une partie du symposium a été consacrée à leur étude. Le
Professeur Otto Glatter (Université de Graz) a commencé par
une description des ISASomes (Internally Self-Assembled Emul-
sions) et de leur obtention. L’émulsification des phases cristal-
lines liquides et notamment des phases cubiques bicontinues
mène dans certaines conditions à des émulsions dont la phase
dispersée est confinée et hautement organisée : les fameux
cubosomes. Des émulsions W/O contenant des fractions volu-
miques d’eau très importantes peuvent être obtenues par
ajout d’une phase huileuse qui solidifie au contact de l’eau.
Dans la suite des dispersions, le Docteur Yves Chevalier du
LAGEP (UCB Lyon1) nous a rappelé les grandes règles de la
formulation des émulsions de Pickering, émulsions sans ten-
sioactifs, stabilisées par des particules solides grâce aux pro-
priétés de mouillage partiel aux interfaces ; il nous a exposé
leur intérêt pour véhiculer dans la peau des substances actives
qu’elles soient hydrophiles ou lipophiles. Un « warning » con-
cernant l’utilisation des poudres a été exposé par le Professeur
Nancy Monteiro (Université de Caroline du Nord) qui nous a
présenté une conférence axée sur la dermatotoxicologie des
nanoparticules appliquées sur la peau et la toxicité qu’elles
engendrent par interactions avec les lipides épidermiques et
les kératinocytes. De nombreuses questions se posent quant à
leur passage et leurs localisations potentielles dans la peau en
fonction de leur état de surface, de leur charge et de la formu-
lation qui les transporte. Le sujet est compliqué d’autant que
les poudres à usage cosmétique se fonctionnalisent ainsi que
l’a montré le Professeur Daniele de l’IRCE Lyon (UCB Lyon1)
qui synthétise des Smart Functional Nano-materials, c’est à
dire des particules inorganiques greffées d’intérêt comme des
particules de TiO2/PABA (acide para-aminobenzoique). Que
serait le maquillage sans la couleur ! La couleur et sa percep-
tion ont été les sujets traités lors de la conférence du Dr Burr
(Ecole des Mines d’Albi). Dans sa conférence le Docteur Burr a
expliqué que la couleur d’un objet peut être prédite et dépend
de la taille des particules, leur indice de réfraction mais aussi
du facteur de forme des particules élémentaires (paramètre
d’arrangement), de leur coefficient d’absorption et bien sûr de
la réflectance. Cependant, la granulation et la compaction
modifient la réflectance et donc l’intensité de la couleur sans
que l’on sache si c’est la formulation, le procédé ou la taille
des grains qui sont responsables de ces changements. Il nous a
présenté une argile de forme fibreuse structurée, la Sépiolite,
qui peut servir de matrice pour incorporer des molécules orga-
niques colorées dans ses cavités. Le Docteur Bureau (Directeur
du Laboratoire Pilote et Industrialisation de chez Chanel) a
insisté sur les aspects techniques de la formulation des
poudres et a expliqué la difficulté de garder les caractéris-
tiques de toucher et de couleur après le compactage en fonc-
tion des ingrédients et notamment des liants. La porosité,
l’élasticité, le transfert, l’état de surface, la force appliquée,
autant de paramètres à prendre en compte avec des pigments
qui peuvent être traités ou non. En terme de nouvelle techno-
Centre des Congrès de Lyon
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9 8
logie, le Docteur Imazeki (Société Miyoshi Kasei) nous a ins-
truits dans sa conférence sur les pigments interférentiels desti-
nés à corriger la réflectance d’une peau atone ou encore à
flouter les rides. La société Miyoshi travaille sur l’obtention de
nanocomposites avec un arrangement cristallin hautement
structuré mimant celui des opales naturelles permettant alors
d’obtenir des propriétés optiques d’intérêt.
Enfin que serait la cosmétologie sans la perception des tex-
tures. Le docteur Eric Perrier (Directeur de la Recherche du
groupe LVMH Parfums & Cosmétiques) nous a exposé les mé-
thodologies mises en place pour comprendre, mesurer et tra-
duire la sensorialité des produits avec des mappings impres-
sionnants pour cibler le meilleur produit à l’échelle internatio-
nale. Ce fut un congrès passionnant avec des thématiques
variées et inhabituelles qui a été bien apprécié par les congres-
sistes !
M.A. Bolzinger et S. Briançon
Université Claude Bernard Lyon 1
The Skin & Formulation Symposium represents a unique mee-
ting point between biologists, pharmacologists, chemists and
physicians dealing with the interactions between skin and the
formulations applied on it: a meeting point between basic
research and cosmetic applications. The Symposium, which
celebrated its fourth edition this year, after Paris in 2003 and
Versailles in 2006 and 2009, was co-organised by the Associa-
tion de Pharmacie Galénique Industrielle / International Socie-
ty of Drug Delivery Sciences and Technology (APGI) and the
European Centre of Dermocosmetology (CED). This year 240
delegates attended the Symposium and around 100 abstracts
and posters were presented. The speeches, held at the highest
scientific level, were organised in four main sections: “Skin
structure and biology”, “In silico, in vitro and in vivo evalua-
tions”, “Formulation and trends for Topical delivery” and, last
but not least, “Powder technology”. To complete the sympo-
sium a poster session depicted around one hundred
researches in the fields of formulation trends for topical deli-
very, in silico in vitro and in vivo evaluations and skin per-
meation. A series of abstracts were selected and presented
orally by their authors during the course of the symposium and
one poster was selected and awarded. This year the poster
award was won by Mirjam Gosenca, Biljana Govedarica and
Mirjana Gašperlin (University of Ljubljana, SL) for the poster
entitled: “Atomic force microscopy study of keratinocytes’
ATOMIC FORCE MICROSCOPY STUDY OF KERATINOCYTES’ CY-
TOMECHANICAL PROPERTIES INFLUENCED BY LAMELLAR LI-
QUID CRYSTALS
Mirjam Gosenca, Biljana Govedarica, Mirjana Gašperlin
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7,
Ljubljana, Slovenia
E-mail: [email protected]
Purpose: To investigate the effect of lyotropic liquid crystals (LC)
with lamellar structure as potential dermal delivery system on
keratinocytes employing atomic force microscopy (AFM) as inno-
vative technique to characterize surface and rigidity (the Young
modulus) of treated cells.
Methods: Keratinocytes’ morphological evaluation is performed
4h post-treatment with 0.45 mg/ml solution of lamellar LC, com-
posed of lecithin/Tween 80/isopropyl myristate/water using
AFM imaging. For stiffness evaluation, AFM nanoindentation is
performed and Young’s moduli are determined.
Results: Treatment with lamellar LC preserved domed and turgid
cells with distinct areas of nucleus and cytoplasm and cells main-
tain their characteristic polygonal shape, but resulted in forma-
tion of nanofibrils. Magnification of the cell membrane reveals
small roundish protruding structures, but this are commonly
observed artefacts due to the cells’ fixation. Results of local AFM
nanoindentation reveal that Young’s moduli, calculated accor-
ding to the Hertz model, of the treated cells are decreasing, i.e.
the keratinocytes become less rigid after 4h exposure to tested
lamellar LC formulation.
Conclusions: Nanofibrils, typical for weakly connected and highly
migrated cells that could also be related to communication chan-
nels between them, are observed following cells’ exposure to
lamellar LC. However, no evident morphological alternations
such as membrane invagination or rounding of the cells are de-
tected. The most pronounced effect of lamellar LC system is
reflected in decreased rigidity of cell membrane as observed
using AFM nanoindentation. This effect is due to surfactants
interaction with the membrane that induces hypoviscosity of the
lipids and enhances membrane fluidity.
Abstract of the awarded poster
International NewsInternational NewsInternational News
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cytomechanical properties influenced by lamellar liquid crys-
tals”.
The Symposium was opened by François-Noël Gilly, President
of the University Claude Bernard, Lyon 1, France and Jürgen
Siepmann, President of APGI and Dominique Bouvier, Presi-
dent of CED.
SKIN STRUCTURE AND BIOLOGY
Joke Bouwstra of the Leiden University (Holland), spoke about
the skin barrier function in patients with atopic eczema (AE), a
chronic relapsing inflammatory disease prevalent in children.
In the speech she gave an introduction on the stratum cor-
neum lipid lamellae organisation and its role in the skin barrier
function. AE is characterized by a reduced barrier function,
which makes the skin more permeable to allergens. A clear
correlation between the disease and the alteration of the lipid
and ceramide composition in skin was evidenced in the
speech.
Marek Haftek, University Claude Bernard, Lyon (France), gave
an insight on the stratum corneum structure and the role of
tight junctions in its organisation and layering. Ultrastructural
studies by means electron microscopy (EM) and immuno-gold
labelling applied to EM were performed to analyze how the
organisation of tight junctions influences the stratum corneum
formation, its layering and its response to stress treatments.
Arlette Baillet-Guffroy, University of Paris Sud (France), pro-
vided a speech on Raman and infrared (IR) spectroscopy ap-
plied to the investigation of cutaneous lipids and the skin bar-
rier function. Raman and IR spectroscopy together allow per-
forming a non-destructive analysis providing unprecedented
insight into the composition, conformation, organisation and
interactions of cutaneous lipids. During the talk, three case
studies were illustrated, on skin composition in Africans and
Caucasians as a consequence of different climate exposure and
food habits, on the perturbation of the barrier function after
UVB irradiation and on the changes of the barrier function
during ageing.
IN SILICO, IN VITRO AND IN VIVO EVALUATIONS
Thomas Föster, Henkel AG & Co. KGaA (Germany), gave a
speech on the uses of tissue engineering technologies in the
field of safety and efficacy testing of cosmetics. The talk pro-
vided an overview of the state of technology of reconstructed
tissues for safety assessment like, e.g., the cornea and epider-
mis models. Moreover, a new model of full-thickness skin,
used to assess novel molecules and products, was presented
along with another model skin containing hair follicles, which
can be used to investigate the effect of actives in hair care.
Philippe Humbert, University of Franche-Comté (France), des-
cribed the latest advances in the field of skin absorption de-
sign. Franz diffusion cells are usually used to assess skin ab-
sorption. Skin absorption is influenced by humidity and tempe-
rature, which leads to different variations throughout the year
and on regional bases but also as a consequence of the living
conditions of individuals. To overcome the variability issue, a
model system has been developed consisting of multiple Franz
diffusion cells mimicking several different temperature and
humidity levels. This kind of device is of great value for the
assessment of the exposure of skin to airborne substances like
solvents.
Ghislain Gangwe Nana, University of Rouen (France), provided
the first of the short communications selected from the abs-
tracts. His talk was focusing on NanoSIMS (Secondary Mass Ion
Spectrometry) 50 imagining technology to study the penetra-
tion of formulations in skin. The technique fully preserves the
skin structure and allows a good imaging of the stratum granu-
losum and the localisation of isotope labelled compounds wi-
thin skin cross sections.
Dominik Selzer, Saarland University (Germany), presented the
second selected abstract and made a dissertation on pharma-
cokinetic models comparing in vivo, in vitro and in silico mo-
dels, demonstrating that mathematical models were able to
predict the results obtained with the in vivo and in vitro mo-
dels.
Jim E. Riviere, North Carolina State University (NCSU) (USA),
provided a keynote lecture about the modelling and the pre-
diction of skin absorption in the case of complex formulations.
Absorption models for drugs and chemicals are usually based
on relative simple model systems. These studies most of the
time, do not reflect real life conditions in which complex mix-
International NewsInternational NewsInternational News
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tures are the norm. Quantitative structure permeability
relationships (QSPR) models have been explored to pre-
dict absorption from liquid vehicles on the basis of the
properties of vehicle components. These complex models
were discussed also taking into account dermal and vas-
cular uptake.
Alexa Patzelt, Humboldt University, Berlin (Germany),
spoke about follicular penetration. Hair follicles represent
an important penetration pathway and a considerable
reservoir of topically applied substances. Multiple para-
meters are affecting permeation besides the molecule in
analysis and the employed vehicle: follicular density, its
size, reservoir and activity status.
Frédéric Crepel, Laboratoires Pierre Fabre Dermocosmé-
tique (France), was the third speaker selected among the
poster presentations. He focused on atopic dermatitis
(AD), a common inflammatory skin disease. Beta-
glycyrrhetinic acid, an active derived from liquorice roots,
has been proven to depict anti-inflammatory, antihistami-
nic and antibacterial properties. The study provided in-
sight in the question of bioavailability of the molecule
upon skin penetration in normal and skin with impaired
barrier functionality. The study concluded that in intact
skin bioavailability remains at a low level, while in infla-
med skin the topical application of a 2 percent prepara-
tion reinforces the functional integrity of the epidermis
and preserves the skin from barrier defects due to inflam-
mation.
Nancy Monteiro-Riviere, North Carolina State University
(NCSU) (USA), gave a lecture on the hot topic of safety
evaluation of nanoparticles and their interactions at the
skin level. Nanoparticles depict unique chemical-physical
properties deriving from their size, which renders them
very interesting potential ingredients from several points
of view. On the other side due to their size nanoparticles
are able to penetrate the skin barrier and to achieve im-
portant effects. As a consequence nanoparticles repre-
sent a potential toxicological risk. Several questions have
been raised in the last years to this regard also because
viability testing is not easy since nanoparticles can inter-
fere with the test results. The talk tried to shed light on
most of these questions.
Thierry Oddos, Johnson & Johnson Santé Beauté (France)
gave the final speech of day one providing an insight on
the effects of formulation on gene expression in skin.
Gene expression is a tightly regulated process, which
responds to a series of environmental and physiological
stimuli and triggers a series of complex modulated reac-
tions. Therefore, skin exposure to determined molecules
could trigger or shut down the expression of genetic path-
ways.
FORMULATION AND TRENDS FOR TOPICAL DELIVERY
The talk of Eric Perrier, LVMH Parfums and Cosmetiques
(France), opened day two of the Symposium. His talk
provided an introduction into the new trends in skin care
and formulation and the associated sensory aspects. Con-
sumer trends vary on a case-by-case basis, from country
to country and even from city to city. Today, when formu-
lating a new product, it has become mandatory to investi-
gate the habits of the potential final users. The impor-
tance of preference mapping of the consumers, analysed
with mathematical models, was discussed.
Otto Glattner, University of Graz (Austria), made a jump
back in the lab and provided an introduction to physical
chemistry – which he brilliantly defined as the science
able to create novel compounds while not modifying co-
valent bounds - of nano-structured emulsions and gels.
Carla Vittorino, University of Coimbra (Portugal), gave the
first speech selected from the abstracts of day two descri-
bing a system for drug delivery employing lipid nanopar-
ticles as transdermal delivery systems.
Yves Chevalier, University of Lyon (France), spoke about
pickering emulsions for drug delivery. These emulsions
are stabilized with solid particles (treated silica particles)
instead of traditional emulsifiers. They have increased
stability and depict several peculiar features. The various
aspects of preparation and materials employed were
discussed. Skin absorption was tested with pickering and
classical emulsions using equivalent comparable systems.
Water/oil and oil/water emulsions were assessed.
Sakine Tuncay Tanriverdi, Ege University, Izmir (Turkey),
gave the second lecture selected from abstracts on the
treatment of onychomycosis, a chronic fungal infection of
the nails, with liposomal gels containing terbinafine hy-
drochloride.
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POWDER TECHNOLOGY
Stéphane Daniele, University Claude Bernard Lyon 1 (France),
described in his talk a series of smart functional materials deri-
ved from molecular engineering. Among these, nanoparticles,
which can be modified and functionalized on their surface.
Efficient coating is not easy, due to technical problems. Several
examples were provided on how nanoparticles could be effi-
ciently achieving excellent results, like in the case of PABA-TiO2
nanoparticles, which depict a broad range UV protection in
sunscreens.
Eric Prouzet, University of Waterloo, Ontario (Canada), lectu-
red the attendants about the “nouvelle cusine in old pots” i.e.
about integrative chemistry applied to inorganic materials in
cosmetics. A constant conflict in cosmetic formulation: it is
necessary to be innovative with final products being conserva-
tive with a limited number of initial ingredients. Several ma-
trices exist which can be used to incorporate. Among these
matrices, mesoporous silica were described.
Alain Burr, MINES Paris Tech CEMEF - UMR, CNRS (France),
spoke about the appearance and the engineering of materials.
Materials can be engineered in order to obtain novel materials
and innovative pigments. Sepiolite (clay) has a channel struc-
ture. Channels could be filled with indigo molecules obtaining
a novel stable colour system to be employed in cosmetics.
Julia Pasquet, Strand Cosmetics Europe (France), presented
the last selected poster on Zinc oxide as a preservative alterna-
tive in cosmetics – parabens usually used to preserve cosme-
tics are subject to huge controversies – the search of novel
preservatives is therefore more actual then ever.
Masafumi Imazeki, Miyoshi Kasei Inc. (Japan), held a speech on
the development of novel approaches to obtain structural
coloured powders based on multi-layer interference pheno-
mena and on their applications.
Finally, Stephane Bureau, Chanel (France), spoke about the
powder technologies as applied by Chanel providing a com-
plete overview on the chemical and physical properties of the
powders.
FLORIAN WEIGHARDT
Household and Personal Care today
TeknoScienze Srl.Publisher
HPC Today: Vol. 7 (3) pages 70-73, July-September 2012
www.teknoscienze.com
9th Central European Symposium on Pharmaceutical Technology Nanopharmaceuticals & Nanomedecine November 20-22, 2012, Dubrovnik, Croatia
The 9th CESPT 2012 is the
continuation of the Central
European Symposium on
Pharmaceutical Technology
started in 1995 by the Slove-
nian Pharmaceutical Society
and that took place in Bled
(Croatia) and which was
organized by Aleš Mrhar
together with his colleagues
from the Ljubljana Faculty of
Pharmacy.
After the 3rd meeting, it was decided to share it with other
central European countries. Following Austria and Hungary,
Croatia was candidate and the beautiful city of Dubrovnik has
been chosen for the 9th symposium.
The Faculty of Pharmacy and Biochemistry of Zagreb, in colla-
boration with Croatian Pharmaceutical Society, was in charge
of the organization of the symposium. We have to ack-
nowledge the tremendous work carried out by Jelena Filipović-
Grčić together with Jasmina Lovrić.
The focus of the meeting was Nanopharmaceuticals & Na-
nomedicine. The topic was divided in 4 main sessions: Poten-
tial of nanomedicines, Nanodiagnostics and further drug deli-
very monitoring, emerging nanopharmaceuticals for non-
parenteral routes, and Protection and bioavailability impro-
vement. A pre-symposium session on the Role of QbD in drug
product development was also organized. Plenary lectures
Pr. Dr. Aleš Mrhar
International NewsInternational NewsInternational News
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were given by Ruth Duncan
(Cardiff, United Kingdom),
Dusica Maysinger
(Montreal, Canada), Lon J.
Wilson (Houston, USA),
Petra Kocbek (Slovenia),
Andreas Bernkop-Schnürch
(Innsbruck, Austria) and
Mauro Giacca (Trieste, Ita-
ly).
Last but not least, the sym-
posium banquet took place
on the beach and was accompanied by enjoyable and dancing
music.
The symposium had a real success, as demonstrated by the
attendance composed of 230 scientists representing total of
510 authors from 32 countries worldwide (United States, Chi-
na, Japan and South Africa). Their presentations occupied 6
plenary sessions, 8 invited lectures and 28 oral sessions, as
well as a total of 147 poster presentations.
The location of the 10th CESPT will be announced in the coming
months.
Pr. Dr. Jelena Filipović-Grčić
Information day APGI – UNIPEX
Controlled Drug & Flavour Release November 20, 2012, CNAM, Paris
After two years UNIPEX was pleased to organize the second
information day with the APGI on 20th November 2012 in Paris.
The meeting was a great success with more than 100 partici-
pants coming from all Europe. Both of APGI as well as UNIPEX
have started the meeting with a great overview on their insti-
tution. Dr. Amelie Bochot from Paris sud (France) has wel-
comed the participants as well as presented an overview on
the International Society of Drug Delivery Sciences and Tech-
nology “APGI”. She also presented journals edited by APGI,
which are the journal of Drug Delivery Science and Technology
and the Gazette. In addition, she showed also the former and
next events organized by the APGI as well as the prices
awarded by the APGI such as Maurice-Marie-Janot award,
APGI thesis award for young scientist and the best paper
award during the 4th symposium in Lyon of skin and formula-
tion which was given to Dr. Mirjam Gosenca from Ljubljana in
Slovenia. She announced the next events including workshops
in 2013/2014 organized by APGI. The next events are 2nd APGI
Coating Workshop, 7th Annual PSSRC “Pharmaceutical Solid
State Research Cluster” Symposium or 3rd Conference on Inno-
vation in Drug Delivery. On the other hand, Chantal Nouri from
UNIPEX has presented all interests and activities of UNIPEX
including Chemical products and manufacturing of pharmaceu-
tical dosage forms. UNIPEX which has worldwide affiliated
company interacts as a manufacturer, distributor as well as a
service provider for cosmetics, chemical and pharmaceutical
products. The information day has been dedicated to different
aspects of drug delivery systems.
The president of the APGI Prof. Dr. Juergen Siepmann
highlighted controlled drug delivery issues in details. He explai-
ned the importance of the optimized drug concentration at the
site of the action in order to achieve optimized therapeutical
effects. Furthermore, he emphasized how to control drug re-
lease in vitro, giving an overview on the most important drug
delivery mechanisms (diffusion, swelling and polymer dissolu-
tion) as well as the classification of the diffusion controlled
drug delivery. He also illustrated how to determine the diffu-
sion coefficients in controlled drug delivery using an analytical
solution of Fick’s second law of diffusion and also another
simple early time approximation of the analytical solution. He
showed how to predict drug release from coated pellets and to
fit of the model to experimental data which can be highly
beneficial for drug delivery development, reducing time and
cost related to experimental data.
Dr. Penz (Head of Technical De-
partment BG Excipients & Techno-
logy, Meggle, Wasserburg, Ger-
many) exhibited an excellent pre-
sentation on Modified Release
formulation with Retalac®. He
showed the advantages of the co-
processed Retalac® (50 % Hydroxy
propyl methyl cellulose and 50 %
SEM Picture of Retalac®
International NewsInternational NewsInternational News
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Lactose) in controlled drug delivery using direct compression.
In addition, the cost and time-consuming of the wet granula-
tion can be avoided when using Retalac as an excipient for the
direct compression. Mathematical models were applied to
quantify drug release from HPMC/lactose-based matrix tablets
loaded with varying amounts of theophylline. Thus, from a
practical point of view, very simple equations can be used
during product optimization, allowing estimating the effects of
formulation parameters on drug release.
Mr. Dizin (Technical expert, France) from Firmenich has pre-
sented advantages of flavor encapsulation and how to per-
ceive flavours. He illustrated different flavours delivery sys-
tems and their advantages, protecting their integrity into the
formulation. He illustrated two important formulations Dura-
rome® and Flexarome® which are innovative drug delivery
from Firmenich. Durarome which is a liquid entrapped into
carbohydrate enhanced and prolonged taste freshness. It en-
sures a perfect
protection against
damage of the fla-
vor after encapsula-
tion which leads to
increased shelf life
avoiding cross con-
tamination.
The second patented technology, Flexarome which is prepared
by gentle extrusion process based on carbohydrate matrix
encapsulation shows different release profile. Furthermore,
Mr. Dizin showed in details how to evaluate drug release and
also to check eventually interactions with matrices using gas
chromatography. However, flavor intensity in confectionary
can be influenced by the matrix and process parameters. Fir-
menich is the industry leading in flavor delivery and encapsula-
tion of flavor for more protection of the activity.
Mr Belmar, from Cafosa has introduced Health in Gum® and
presented release profile of active ingredients from compres-
sed chewing gum. He also showed benefits of chewing gum
including weight loss and stress relief. Health in Gum® is a
ready-to-use powder for pharmaceutical and nutraceutical
chewing gum containing an active ingredient. Chewing gums
with active ingredients are ideally produced with Health in
Gum® as its manufacturing process does not involve high tem-
peratures and its composition has no moisture content. This
excipient was created to simplify the manufacturing process of
compressed medicated chewing gum in a quick and cost-
effective way since it is adapted to direct compression with
standard equipment. He
has presented the im-
pact of excipients used
in chewing gum on its
physicochemical proper-
ties (e.g. sugar esters as
lubricant instead of stea-
rate magnesium).
Mr Robin from Isochem presented Vitamin E TPGS (d-α toco-
pheryl polyethylene glycol 1000 succinate), a multirole exci-
pient used in nutraceutical and pharmaceutical applications.
Vitamin E TPGS has shown proven and recognized properties
to improve bioavailability of poorly absorbed drugs vitamins
micro-nutrients acting as an absorption and permeability en-
hancer and to develop Self Emulsifying Drug Delivery Systems
(SEEDS) for poorly soluble drugs as an emulsifier. As a water
soluble compound, Vitamin E TPGS is also used as an efficient
source of natural Vitamin E, both for therapeutic purposes and
nutrition. In addition Vitamin E TPGS has physical properties
that make it a relevant plasticizer for innovative technologies
in the pharmaceutical industries such as hot melt extrusion.
Durarome® after compression
From left to right : Solid, Melt, 20% water solution, 40% in water gel
Durarome® before compression
International NewsInternational NewsInternational News
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Cross-border Cooperation programme 2007-2013 INTERREG IVA “2 Mers Seas Zeeën” IDEA : Improving Drugs Efficacy and Availability
The IDEA (Improving Drug Efficacy and
Availability) project originates from the
presence in the 2-seas EU region of
some of the world-leading researchers
in the challenging field of solid state
pharmaceutical developmental science.
These scientists work in various fields
(physics, chemistry and pharmacy) at the Universities of Cam-
bridge, East Anglia, Ghent and Lille as well as at a Flemish SME
SEPS Pharma. They group together their complementary scien-
tific know-how and equipment to implement a new activity
which meets the urgent demands of advanced drug delivery
systems and approaches. This innovation-driven research pro-
gramme has important outcomes for public health as well as
for vocational training. It provides a unique opportunity to
position the region as an international leader in the solid state
pharmaceutical field. In addition, it is intended to attract and
support new SME companies in the pharmaceutical area for
whom our consortium will supply world leading technology for
the development of novel drugs. Such biotechnological compa-
nies are dramatically lacking in the region.
The vast majority (80%) of drugs are prepared as solid pro-
ducts (powders, tablets , capsules). These solid systems may
exist in a number of different forms (crystal polymorphs, amor-
phous forms, nanocrystals) which behave differently in the
human body with strong impact on therapeutic efficacy, safety
and profound implications for product registration and pro-
duct stability. Controlling and predicting the solid state proper-
ties during manufacture and on storage are thus major issues
in the development of new pharmaceutical products. This is
particularly pertinent for drugs with poor water solubility
(70 % of new drugs). Newly synthesized drugs for cancer the-
rapy are particularly concerned by this optimization of the
solid state form to be administered to patients. There is thus a
very current awareness for research and training reorientation
so as to incorporate understanding of the solid state chemistry
of drugs and dosage forms to overcome the present empirical
approach.
Our aim is to develop within the EU region an original research
activity programme with technical applications to the design of
new solid state pharmaceuticals, with a view to facilitating the
development of both new and existing drugs in forms with
improved bioavailability, efficacy, chemical and physical stabili-
ty, safety and predictability. The new forms are mainly based
on nanoparticle technologies, amorphous drug forms and
molecular complexations. The participation of a pharmaceuti-
cal company (SEPS Pharma, Ghent) in the project provides fast
and efficient validation of the most innovative developments.
We have created in the region a training centre for a new
trade dedicated to the optimization of the solid-state drug
manufacturing processes. This training is provided jointly by
the members of the partnership. This type of trade meets the
need of pharmaceutical firms in order to overcome the major
bottlenecks of the drug development. This (by nature trans-
disciplinary) training targets students and personnel from local
industries undertaking continuing professional development.
We have implemented a trans-disciplinary (physics, chemistry
and pharmacy) technological platform at the state-of-the-art,
dedicated to: i) material synthesis, ii) advanced characterisa-
tion, iii) formulation of pharmaceutical materials. This will help
establishing the EU region as an attractive choice for compa-
nies developing new drug products.
An IDEA conference will be held on May 14-15 2013 at the
Lille 1 University in Villeneuve d'Ascq, France. It will focus on
presenting the most recent developments in understanding
and controlling the physico-chemical properties of pharmaceu-
tical solids (active substances and excipients) and their impact
on the efficacy and bioavailability of drugs. It will be opened to
scientists and researchers from academia and from industry.
Partners of the IDEA project:
University Lille 1 - France (M. Descamps). Coordinator.
University of Cambridge - UK (W. Jones)
University Lille 2 – France (J. Siepmann)
University of Ghent – Belgium (C. Vervaet)
University of East Anglia - UK (D. Craig)
SEPS Pharma - Belgium (Y. Gonissen)
Contact : Prof. M. Descamps
Unité Matériaux et Transformations
(UMET)
CNRS UMR 8207 - Université Lille 1
BAT P5 – Cité Scientifique
59655 VILLENEUVE D’ASCQ FRANCE
http://umet.univ-lille1.fr
International NewsInternational NewsInternational News
18
Mass spectrometry im
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Time-controlled drug delivery systems are steadily increasing
in importance for pharmaceutical or medical researchers and
clinicians [1]. These devices provide desired release rates and
therefore more efficient treatments over longer periods of
time. However, yet relatively little is known about the under-
lying mechanisms and changes in system structure upon expo-
sure to aqueous media or biological organism. In this context,
new advanced analytical techniques such as mass spectro-
metry imaging [2] can offer some novel information about the
behavior of drug delivery system in biological medium. Mass
spectrometry imaging (MSI) combines the ability of tracking a
molecule within targeted sample (biopsies, necropsies, plants,
implants, etc.) and mass spectrometry which allows broad
range label-free molecule characterization (drugs, metabolites,
lipids, peptides or proteins). The basic principle of MALDI-MSI
is a focused laser beam on a cross-section of the sample which
generates ions. Ions are then detected using a mass spectro-
meter (accelerating the ions an in electric field and separating
them according to their mass to charge ratio, m/z) at each
position (or voxel) to obtain mass spectrum wherein thou-
sands of molecule are visualized. Then, a spectral image of
each molecule can be generated by monitoring the signal in-
tensity of signature ion mass fingerprints specific to each com-
pound and for each voxel. One important parameter of MSI
experiment is the spatial resolution (measured in µm) of the
image. Briefly, it is the distance between two successive voxel
on the mass spectrometric image which depends on the laser
beam focus, its energy as well as on the size of targeted
sample. In the case of MALDI (Matrix-Assisted Laser Desorp-
tion/Ionization) mass spectrometry [3], a specific compound,
the so-called “matrix”, is sprayed on the sample facilitating
proton transfer in order to increase the degree of sample ioni-
zation. The workflow of MSI experiment is presented in Fi-
gure 1.
The main advantages of this technique are:
High specificity: Mass measurement accuracy, spectral
resolution and structural analysis permit to obtain univo-
cal characterization of all molecules observed on mass
spectra.
Untargeted approach: A single mass spectrum gives ac-
cess to thousand ion signals corresponding to individual
ionized molecules.
Sensitivity: Low molecular concentration level can be
reached and correlated with small sample area.
Rapid analysis time: No labeling or purification steps are
needed.
Post-processing and statistical analysis of imaging MS
data: These data treatments are very useful for large
molecule analysis, biomarker hunting or molecular histo-
logy.
Quantification: Different approaches have been recently
developed to address this issue [4, 5].
MSI is now applied in drug discovery and development phases
[6-8] in order to study the efficacy and the toxicity of drugs
and their metabolites in the screening phase, optimization
phase, as well as in “omics” research (metabolomics, lipido-
mics [9], proteomics [10], etc.). This technique has a broad
range of application and is particularly useful, for example, in
oncology (e.g. discovery of disease biomarkers) [11, 12],
ophthalmology (e.g. study of small histological tissue) [13],
dermatology (e.g. penetration of active compound through the
skin) [14] or neurology (e.g. CNS, Central nervous System,
research) [15] but it is not limited to any therapeutic area.
Drug-releasing properties of the implant can be affected by
compositional or structural defects, which can be monitored
using imaging techniques. Drug delivery system composition
or tablet formulation has already been investigated using diffe-
rent techniques included Raman and near infrared (NIR) spec-
Utility of Mass Spectrometry Imaging of Drug Delivery Systems: Cutting Edge of Molecular Imaging Gregory Hamm (Research Manager, PhD), David Bonnel (Project Manager, PhD), Raphael Legouffe (Analytical Engineer) and Jonathan Stauber (CEO & CSO, PhD)
For correspondence: ImaBiotech, Maldi Imaging Service Department, Parc Eurasante , 885 Avenue Euge ne Avine e, 59120 Loos, France – [email protected]
Introduction
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troscopy or magnetic resonance imaging (MRI). Several appli-
cations of MSI have been described in the literature [16-18].
Especially, SIMS (Secondary Ion Mass Spectrometry) and DESI-
MS (Desorption Electrospray Ionization- Mass Spectrometry)
imaging have been largely used to characterize the structure
of advanced drug delivery systems; however, a few example of
MALDI experiment has been applied to the study of this ad-
vanced drug delivery. The proof of principle study demons-
trates the utility of MALDI-MSI in a new field of pharmaceutical
research, providing new insight into the spatial and kinetic
distributions of the pharmaceutical compounds in advanced
drug delivery systems [19].
Sample Preparation and Acquisi-
tion for MS Imaging.
Glyceryl tristearate (Dynasan 118) and theophylline were
wetted with aqueous Poloxamer 407 solution and extruded
with a piston extruder to obtain strings, which were then cut
into cylinders (1mm in diameter) as shown in Figure 2. Control
and exposed (after 3 or 14 days) implants containing various
amounts of theophylline (0, 2.5, 5 and 10 %, w/w) were used
in this imaging MS study. Drug release was measured in phos-
phate buffer pH 7.4 at 37 °C (80 rpm). At pre-determined time
points, samples were withdrawn, freeze-dried and stored at –
80 °C until further analysis.
A key parameter of our study is the sample preparation: we
introduced an adapted method for the analysis of implants via
MSI. Adhesive acetate tape is pressed gently onto implant, and
afterward, embedded in a 3 % gel of carboxymethyl cellulose
(CMC, Sigma-Aldrich, St. Louis, MO), then fast frozen using
liquid nitrogen, unmolded and stored at -80°C. Before cutting,
a piece of adhesive acetate tape was pressed gently onto em-
bedded implant in CMC gum in order to keep the integrity of
the section. Cross and longitudinal implants sections of 25 µm
thick were carried out using a Microm cryostat HM560
(Thermo scientific) operating at -25°C. The combination of
adhesive acetate tape and implant section was then mounted
on conductive indium-tin-oxide (ITO) glass slide (Bruker Dalto-
nics, Bremen, Germany) covered by double-side adhesive tape.
Figure 1. Schematic outline of a typical workflow for MALDI-MSI; Sample sectioning (a) and mounting (b) on a conductive
slide. (c) Automated method for MALDI matrix deposition onto sample section for increased homogeneity. (d) Mass spec-
trometry experiment; Ionization step using a laser beam which fires the sample following a virtual raster and with a specific
spatial resolution. (e) Mass spectra generated for each x, y coordinates or each voxel. (f) Overall mass spectrum resulted
from the sum of all mass spectra recorded for each position of the virtual raster. Selection of a single m/z value (red, blue or
green ion) on resulting spectrum. (g) Optical scan image of targeted sample section and visualization of the distribution of
three specific ions (red, blue and green) on two dimension MS image.
Figure 2. Molecular structure of theophylline (a) and
macroscopic image of the resulting implant (b)
20
ITO glass slides were removed from deep freeze after 30 min
and immediately transferred to a desiccator for 20-25 min.
Optical images of each implant sections were acquired using
an HP scan (Hewlett-Packard, Palo Alto, CA). A solution of 2,5-
dihydroxybenzoic acid serving as a matrix former (2,5-DHB, 40
mg/mL) in a 1:1 (V/V) mixture of methanol:water containing
0.1 % TFA was used for matrix deposition in this study. The
matrix solution was sprayed onto the implant sections using
the SunCollect automatic sprayer (SunChrom, Friedrichsdorf,
Germany). The matrix deposition onto the implant section
was performed at 10 μL/min flow rate between layers to
achieve 10 layers.
MS images were obtained using an AutoFlex speed LRF MALDI-
TOF mass spectrometer (Bruker Daltonics, Bremen, Germany)
equipped with a Smartbeam II laser used at a repetition rate of
1000 Hz. All parameters were optimized before the imaging
experiment on standard sample of theophylline (C7H8N4O2,
[M+H]+ m/z 181.1) was run. Positive mass spectra were acqui-
red in the 0–1000 m/z range. The mass spectrometer was
operated in the reflectron mode and the mass spectrum obtai-
ned for each position of the images corresponds to the avera-
ged mass spectra of 500 consecutive laser shots on the same
location. An image raster step of 50 µm was selected for ima-
ging of theophylline implants. FlexControl 3.0 and FlexImaging
2.1 software packages (Bruker Daltonics, Bremen, Germany)
were used to control the mass spectrometer, set imaging para-
meters and visualize imaging data.
1. Reference Study of Drug Delivery
System
The first step of our study was to evaluate the homogeneity of
the active drug distribution, i.e. theophylline into the implants
and the stability of the implant during the imaging sample
preparation and experiment. A key issue of all imaging analy-
sis is the sample preparation, in this particular case, two set of
adhesive tape were necessary in order to keep the integrity of
the implant cryo-section.
Figure 3 shows an optical and MALDI-MS image of a longitudi-
nal and radial cross-section of a Dynasan 118 (glyceryl tristea-
rate) based implant loaded with 5 % theophylline before expo-
sure to the release medium. The cross-section was obtained in
the middle of the cylindrical implant, but radial cross-sections
at other levels were very similar (data not shown). Figure 4
illustrates on the right hand side exemplarily a mass spectrum,
indicating the composition of the respective pixel highlighted
in the MALDI-MS image of the same implant drug loading. The
mass spectrum (Figure 3e) allows for the identification of the
intact theophylline ion at m/z 181.1. The drug studied can be
clearly observed both in the spectra and in the images as pro-
tonated molecules, [M+H]+. No endogenous species such as
matrix peaks were detected in the mass range of theophylline
ion (control implant 0 %,Figure 4). The color scale used in the
MALDI-MS image on the left hand side reflects the relative
intensity of the MS signal of the theophylline ions at the va-
Figure 3. Optical image (top) and MALDI- MS image (bottom) of a longitudinal (a, b) and radial (c, d) cross-section of a Dynasan
118 (glyceryl tristearate) based implant loaded with 5% theophylline before exposure to the release medium. Distribution of
theophylline related ion at m/z 181.1 with a lateral resolution of 50 µm. On the right hand side (e) the mass spectrum of a
particular position is shown, with a zoom illustrating theophylline-related ions (adapted from Kreye et al., 2012[19]).
New TechnologiesNew TechnologiesNew Technologies
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Mass spectrometry im
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Mass spectrometry im
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rious positions, warm color for the maximum and cold color
for minimum. MALDI-MS images reveal that the theophylline
is homogeneously distributed within the delivery system at the
macroscopic level, however, a significant local concentration
differences exist. However, the longitudinal implant cryo-
section was less useful to evaluate the distribution of theo-
phylline ion because of the difficulty to keep the integrity of
the implant for MSI. Moreover, these MS images provide also
some information about the localization of Dynasan 118 distri-
bution within the implant (data not shown). The polymer ion
([M+H]+, m/z 913.3) highlighted the same behavior as the ac-
tive drug in terms of homogeneity.
Figure 4 shows the distribution of m/z 181.1 (theophylline
base [M+H]+ ion) throughout several radial cross-sections of
Dynasan 118 based implants loaded with a gradient of theo-
phylline concentration (0, 1, 2.5, 5, or 10%). All ion intensity
scales were the same in order to evaluate the impact of theo-
phylline concentration on the MS signal. Importantly, these
experiments can provide semi-quantitative information about
theophylline response and it is feasible to generate a pseudo
calibration range using these samples. We observed that the
correlation between ion intensity per surface unit and theo-
phylline concentration is quite linear (data not shown). Clear-
ly, this method using pseudo “gold-match standard” appears
to be useful to quantify theophylline concentration into the
implant after the exposure upon the bulk medium. Further-
more, this technique delivers important information on the
inner structure of the investigated controlled release implants
without adding any marker (the chemical composition of the
device, which can be identified at every position in the im-
plant, disturbing signal intensity.
2. In vitro Drug Release Studies
The second phase of this study was to follow the drug release
behavior of the implant upon exposure to the dissolution me-
dium (phosphate buffer pH 7.4). Figure 5 shows the macrosco-
pic i impact of the dissolution medium, the implant was expo-
sured (a) and on the other hand, the consequences at the
molecular level on theophylline relative concentration (b).
The latter aspect of the implant after exposure (Figure 5.a”at
the bottom”) compared with the initial form clearly (Figure
5.a.”at the top”) shows that its surface became more porous
but remained partially intact. The porosity of the surface can
be at least partially explained by the leaching out of the drug
from the system. Moreover, the pores were homogeneously
distributed, indicating homogenous drug content in all parts of
the implant. To correlate the macroscopic observation with
the molecular aspect, MSI experiments have been performed
on implants exposed to release medium (loaded with 2.5 %
and 5 % of theophylline and exposed during 0, 3 and 14 days).
For each implant on MS images, mean intensities were ex-
tracted on the entire surface, normalized and plotted in a
graph for reasons of comparison (Figure 5.b). A decrease in
concentration of theophylline was observed, which can be
attributed to the leaching out of the drug from the implant
into the release medium.
MALDI-MSI was also used to better understand the dynamic
changes in the inner implants’ structure during drug release.
Figure 6 shows optical images (top raw), MS images (middle
Figure 4. Optical images (top) and MALDI- MS images
(bottom) of radial cross-sections of Dynasan 118
(glyceryl tristearate) based implant, loaded with 0, 1,
2.5, 5, or 10% theophylline before exposure to the
release medium (adapted from Kreye et al., 2012[19]).
Figure 5. (a) Macroscopic pictures of implants loaded
with 10 % theophylline: (1) before exposure to the re-
lease medium, and (2) after 90 days of exposure to phos-
phate buffer pH 7.4 at 37 °C. Two different implants are
shown in (1) and (2). (b) Relative intensity histogram of
theophylline ions within the implants initially loaded
with 2.5 and 5 %, after 0, 3 and 14 days exposure to the
release medium.
New TechnologiesNew TechnologiesNew Technologies
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Mass spectrometry im
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22
raw) and peak intensity distance profiles (bottom raw). The
latter were obtained from the MS images, considering both
theophylline ion peaks illustrated in the blow-up in Figure 3e
and the regions highlighted in the middle raw of Figure 6b.
The implants were exposed to phosphate buffer pH 7.4 for 3 or
14 d, as indicated. Note that the scale of the y-axis changes
from the left to the right in order to keep a better visualization
of the different signal intensities. For reasons of comparison,
also implants before exposure to the release medium are illus-
trated (left column). Clearly, MALDI- MS imaging allows for a
detailed monitoring of the changes in drug concentration as a
function of time and position. Importantly, the results show
that drug distribution at the lower micrometer level remains
highly heterogeneous and that drug depletion starts in the
surface-near regions, continuously progressing towards the
center of the lipid implants. This crucial information can be
used for a better understanding of the underlying drug release
mechanisms.
Conclusion
MALDI-MSI can offer new insight into the inner structure of
advanced drug delivery systems, as well as the changes in the
drug distribution before and after the exposure to the release
medium. MSI allows in-situ analysis of drug loaded delivery
systems which allows the measurements of the molecular
composition at the micrometer scale. This crucial information
allows for a better understanding of the underlying drug re-
lease mechanisms and the enhancement of the bioavailability
as well as the efficiency of drugs. The next step will be the
monitoring of the new developed drug delivery system in vivo
in order to be closer to the pathophysiological conditions,
which can impact the drug release behavior in vivo.
Acknowledgement
The authors are grateful for the fruitful collaboration with the
INSERM U 1008 on lipid implants.
References
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chanisms of compressed lipid implants. International
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Figure 6. Investigation of the behavior of implants
loaded with 2.5 % theophylline exposed to phosphate
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phylline ion distribution. (c) Peak intensity distance pro-
files of theophylline ions (adapted from Kreye et al.,
2012[19]).
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Colloidal carriers for dermal delivery
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Effect of colloidal carriers on ascorbyl palmitate
dermal delivery Mirjam Gosenca, Mirjana Gašperlin
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Introduction
SMES w/o ME LLC
It is a scientific fact that oxidative stress plays an important
role in skin ageing, diseases and disorders. Successful prophy-
laxis and therapy would necessitate control of oxidant/
antioxidant balance at the affected site that can be achieved
through topical administration of antioxidants. Even though
the latter is not a new concept several obstacles must be over-
come regarding physicochemical and biopharmaceutical prop-
erties of the antioxidant agent such as low solubility, poor
permeability, and/or high instability. Two main approaches for
optimized dermal delivery are recognized, namely chemical
modification of antioxidant molecules and/or using novel drug
delivery systems [1-3].
Ascorbyl-palmitate (AP), a lipophilic derivative of ascorbic acid,
is used in topical preparations in order to prevent oxidative
damage of biological components of the skin [4]. It is recogni-
zed by improved skin penetration and better stability compa-
red to ascorbic acid. However, AP features could still be en-
hanced when incorporated in suitable delivery system that is
reflected in many studies investigating colloidal lipid carriers
such as microemulsions, liposomes, solid lipid nanoparticles
and nanostructured lipid carriers for enhancing Ascorbyl-
palmitate antioxidant activity, stability and/or skin penetration
[4-6].
In this context, our study focuses on AP bioavailability when
incorporated in lyotropic liquid crystals with lamellar structure
(LLC), microemulsion (ME) and self-microemulsifying system
(SMES). LLCs and MEs show great potential as delivery sys-
tems, especially for facilitating drug transport into the skin,
improving drug stability, and also due to high solubilisation
capacity and thermodynamic stability. LLCs are formed by
surfactants (more precisely their hydrates or solvates) in the
presence of a water and/or oil phase. MEs are defined as ther-
modynamically stable, transparent, low-viscosity dispersions
of water, oil, and surfactant (and cosurfactant) molecules. LLCs
and MEs can be formed upon dilution of SMES – a mixture of
oil and surfactants – with water [7-10].
The objective of our study was to investigate the potential of
phase transition systems formed upon dilution of a SMES with
an aqueous phase for AP dermal delivery. The AP solubilisation
capacity of colloidal systems that differ in water content and
New TechnologiesNew TechnologiesNew Technologies
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Colloidal carriers for dermal delivery
24
consequently in internal microstructure and viscosity was eva-
luated. Influence on Ascorbyl-palmitate skin deposition was
examined using isolated pig ear skin as the most relevant in
vitro animal model for human skin.
Materials and Methods
A pseudoternary phase diagram was constructed for IPM, a
lipophilic phase, (Tween 80/lecithin = 1: 1) / butanol = 1:1, a
surfactant / cosurfactant mixture, and water using water titra-
tion technique. IPM and Tween 80 were obtained from Fluka,
Sigma-Aldrich GmbH, Germany, lecithin (Lipoid S-100) from
Lipoid GmbH, Germany and butanol from Riedel-de Haën,
GmbH & Co. KG, Germany. Monophasic mixtures of Tween 80,
lecithin, butanol, and IPM were titrated with aliquots of distil-
led water and stirred at 25 °C. After equilibrium was reached,
the mixtures were visually checked for transparency. Clear,
isotropic one-phase systems of low viscosity were considered
to be either w/o (lipophilic) or o/w (hydrophilic) MEs. The
distinction was based on conductivity measurements and co-
balt chloride test paper results. Systems with turbid ap-
pearances were considered to be coarse EMs. A pseudoternary
phase diagram of the same components, but without butanol
was previously constructed and visually clear samples of high
viscosity were confirmed as LLC systems with polarization mi-
croscopy [11]. For our study, formulations along the dilution
line with surfactant mixture / IPM = 60 / 40 were selected,
including SMES and w/o ME, as well as LLC on an equivalent
dilution line. The compositions of the formulations tested are
shown in Table 1.
Table 1: Composition of tested formulations (% w/w).
** indicating surfactant/co-surfactant mixture (Tween 80/ lecithin = 1:1)/butanol = 1:1 * indicating surfactant mixture Tween 80/lecithin = 1:1
The viscosity of the selected systems was determined using a
SV-10 Vibro Viscosimeter (A&D Company, Japan) at 25 °C.
The solubilisation capacity of selected systems was determi-
ned by adding an excess amount of AP to formulations that
were allowed to reach equilibrium by stirring at 20 ± 1 °C.
Subsequently the samples were centrifuged and the superna-
tant was analyzed for AP concentration using HPLC [12].
For the skin permeation studies, Franz diffusion cells were
used (diffusion area of 0.785 cm²). 8 ml of 0.9 % NaCl contai-
ning 0.5 % Brij 98 and 0.01 M Na2S2O3 was used as a receptor
fluid. 1 g of the tested SMES, w/o ME, and LLC loaded with AP
(at 1% or at maximum solubilisation concentration) was ap-
plied to skin surface. At predetermined time intervals (every
hour up to 6 hours) 1 ml of receptor sample was withdrawn
and replaced with fresh receptor fluid. After 6 hours the epi-
dermis was separated from the dermis by heat treatment and
AP was extracted with methanol. The samples were analyzed
using HPLC. The experiment was conducted in quadruplicate.
The results are represented as the cumulative amount of As-
corbyl-palmitate permeated per surface area.
Results
Various systems can be obtained when combining IPM,
(Tween 80/lecithin)/butanol as a surfactant/co-surfactant
mixture and water in different ratios (see Fig. 1). Upon dilution
of the SMESs, water-free mixtures of oil phase and surfactants,
both types of MEs (w/o and o/w) and EMs are formed. Regions
of w/o MEs were formed at higher surfactant content, while
EMs were formed at water-rich regions together with relative-
ly small areas of o/w MEs.
Figure 1: Pseudoternary phase diagram of Tween 80/
lecithin/butanol, IPM, and water. Empty circles repre-
sent w/o MEs, filled circled o/w MEs and lines EMs.
Systems included in permeation studies are indicated
on the selected dilution line with filled circles. * indicating the surfactant mixture Tween 80/lecithin = 1:1
SMES w/o ME LLC
surfactant mixture 60** 55** 45*
IPM 40 35 30
water 0 10 25
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Colloidal carriers for dermal delivery
Colloidal carriers for dermal delivery
25
A SMES containing 60 % of surfactant/co-surfactant mixture
and 40 % of IPM and w/o ME on its dilution line were further
evaluated together with a LLC system that was obtained on
the same dilution line at 25 % water, but without butanol. For
latter system LLC structure was confirmed due to characteristic
“Maltese cross” texture (Fig. 2). Namely, lecithin is too lipo-
philic to form MEs in the absence of butanol as a co-
surfactant, and has a strong tendency to form liquid crystal
structures.
The AP solubilisation capacity was the highest in the SMES
followed by the w/o ME and LLC system (Table 2). The inverse-
ly proportional relationship between solubilisation capacity
and water content in systems could be explained by the lipo-
philic character of AP. Formulations differed also in viscosity
values (Table 2), being evidently lower for the SMES and the
w/o ME compared to LLC system where interactions of cylin-
drical or worm-like micelles when water is added to lecithin
reverse micelles in apolar solvents tend to give rise to high
viscosity systems [9].
Table 2: Ascorbyl-palmitate solubilisation capacity and viscosi-
ty of tested formulations.
In order to evaluate both the carrier system and the Ascorbyl-
palmitate loading concentration on AP skin deposition, the
amount of AP accumulated in the epidermis and dermis was
distinguished with regard to carrier system and the quantity of
AP incorporated (either 1 %, a level of AP that is essential to
obtain desired effects in the skin, or the maximum solubilisa-
tion concentration; Fig. 3).
The results of Ascorbyl-palmitate skin deposition show relati-
vely high concentrations of AP delivered to tested skin layers,
especially to epidermis, whereas no AP was found in receptor
fluid. It is presumed that AP bound to skin tissue forms a very
strong reservoir. At concentration of 1 % increased permeation
was observed for LLC compared to the SMES and w/o ME.
However, at maximum solubilisation capacity, the highest
permeation was observed for the SMES, most probably due to
its highest concentration gradient promoting AP transport into
the skin. Nevertheless, a considerable amount of AP was also
found in skin layers when using LLC, especially when conside-
ring significant difference in AP solubilisation capacity of both
systems. Improved permeation can be attributed to ability of
LLC system to fluidize intercellular lamellar lipids as a result of
structure similarity; this effect is currently investigated by our
research group using atomic force microscopy.
Conclusion
The Ascorbyl-palmitate skin permeation was influenced by
both, microstructure as well as solubilization capacity of tested
systems. The LLC system was proven as the most suitable sys-
tem taking into account high Ascorbyl-palmitate permeation
together with the most convenient texture for dermal applica-
tion.
Figure 3: Ascorbyl-palmitate deposition in the epider-
mis and dermis from the tested formulations (mean ±
SD, n = 4).
Figure 2: Polarized light micrograph of LLC; an arrow
indicates Maltese cross.
Solubilisation capacity (%)
Viscosity
SMES 16.04 8.18 mPas
w/o ME 11.69 11.6 mPas
LLC 6.90 2.87 Pas
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Colloidal carriers for dermal delivery
26
References
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examination of clinical methods in the assessment of
ageing skin. Part I: cellular and molecular perspectives of
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tems in developing topical antioxidants as therapeutics to
combat photoageing. Ageing Res. Rev. 2007, 6, 271-288.
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antioxidant vitamins through the skin to prevent skin
ageing. Expert Opin. Drug Deliv. 2011, 8(7), 905-919.
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against ultraviolet induced free radicals with ascorbyl pal-
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7. Date A.A., Patravale V.B. – Microemulsions: applications in
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8. Makai M., Csányi E., Németh Z.S., Pálinkás J., Erős I. - Struc-
ture and drug release of lamellar liquid crystals containing
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novel drug delivery systems. – Adv. Drug Deliv. Rev. 2000,
45, 89-121.
10. Burducea G. - Lyotropic liquid crystals I. Specific structures.
– Rom. Rep. Phys. 2004, 56(I), 66-8.
11. Gosenca M., Gašperlin M. Lecithin based pseudoternary
phase diagrams. 8th Central European Symposium on Phar-
maceutical Technology, September 16-18 2010, Sci.
Pharm., 78(1), 690.
12. Gosenca M., Obreza A., Pečar S., et al. A new approach for
increasing ascorbyl palmitate stability by addition of non-
irritant co-antioxidant. AAPS Pharm. Sci. Tech. 2010, 11(3),
1485-1492.
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