university of lille, lille, franceamptec.univ-lille1.fr/idea/gazette_dec.pdf · university of...

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

http://www.sanofi.com/rd/rd.aspx

http://www.merckmillipore.com/

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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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2

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:

[email protected]

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

http://www.excipients-academy.basf.eu/Home.aspx

http://www.gattefosse.com/

http://www.abbott.com/index.htm

http://www.colorcon.com/

mailto:[email protected]

http://www.apgi.org/coating_WS

http://www.univ-lille2.fr/accueil.html

http://pharmacie.univ-lille2.fr/accueil.html

http://interreg4a-2mers.eu/en

http://www.inserm.fr/

http://www.drugdiscoverylille.org/

http://www.biogrund.com/

http://www.gamlen.co.uk/

http://www.ima-pharma.com/

http://www.loedige.de/

http://www.merckmillipore.com/

http://www.sheffieldbioscience.com/

http://www.sternmaid.de/english/index.html

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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?



http://www.pssrc.org/

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5

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

http://www.apgi.org/documents/PisaFlyer1st_000.pdf

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5

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

[email protected].

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






http://www.apgi.org

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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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http://apgi.org/frform1.htm



http://apgi.org


http://www.sanofi.com/rd/rd.aspx

http://www.apgi.org/

http://www.enstimac.fr/

http://www.castres-mazamet-technopole.fr/

http://www.buchi.com/

http://www.hovione.com/

http://www.thermofisher.com/global/en/home.asp

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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


10

8

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


11

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


http://en.sanofi.com/index.aspx

12

10

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-


13

11

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.


14

12

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


15

13

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®


16

14

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


http://www.isochem.eu/

http://www.meggle.com/en/

http://www.firmenich.com/

http://www.cafosa.com/EN/Default.aspx

17

15

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

[email protected]

http://umet.univ-lille1.fr



http://umet.univ-lille1.fr

http://idea.univ-lille1.fr/

http://interreg4a-2mers.eu/en

18

Mass spectrometry im

aging

New TechnologiesNew TechnologiesNew Technologies


aging

16

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


http://www.imabiotech.com/?lang=fr

19


aging


17

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]).


18


aging


aging

21

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.


19


aging

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

1. Kreye F, Siepmann F, Siepmann J: Drug release me-

chanisms of compressed lipid implants. International

Journal of Pharmaceutics 404(1-2), 27-35 (2010).

2. Caprioli R, Farmer T, Gile J: Molecular imaging of biologi-

cal samples: localization of peptides and proteins using

MALDI-TOF MS. Anal Chem 69(23), 4751-4760 (1997).

3. Karas M, Hillenkamp F: Laser desorption ionization of

proteins with molecular masses exceeding 10,000 dal-

tons. Anal Chem 60(20), 2299-2301 (1988).

4. Hamm G: Toward Quantitative Imaging Mass Spectro-

metry. Spectroscopy, (2012).

5. Hamm G, Bonnel D, Legouffe R et al.: Quantitative mass

spectrometry imaging of propranolol and olanzapine

using tissue extinction calculation as normalization factor.

Journal of Proteomics (0), (2012).

6. Solon Eg, Schweitzer A, Stoeckli M, Prideaux B: Autoradio-

graphy, MALDI-MS, and SIMS-MS imaging in pharmaceuti-

cal discovery and development. Aaps J 12(1), 11-26

(2010).

7. Castellino S, Groseclose Mr, Wagner D: MALDI imaging

mass spectrometry: bridging biology and chemistry in

drug development. Bioanalysis 3(21), 2427-2441 (2011).

8. Bonnel D, Legouffe R, Willand N et al.: MALDI imaging

techniques dedicated to drug-distribution studies. Bioa-

nal. 3(12), 1399-1406 (2011).

9. Touboul D, Brunelle A, Laprevote O: Mass spectrometry

imaging: Towards a lipid microscope? Biochimie 93(1),

113-119 (2011).

10. Franck J, Longuespee R, Wisztorski M et al.: MALDI mass

spectrometry imaging of proteins exceeding 30,000 dal-

tons. Med Sci Monit 16(9), BR293-299 (2010).

11. Stauber J, Lemaire R, Franck J et al.: MALDI imaging of

formalin-fixed paraffin-embedded tissues: application to

model animals of Parkinson disease for biomarker hun-

ting. J Proteome Res 7(3), 969-978 (2008).

Figure 6. Investigation of the behavior of implants

loaded with 2.5 % theophylline exposed to phosphate

buffer pH 7.4 (after 0, 3 and 14 days). (a) Optical scan

image of the implant and (b) related MS images of theo-

phylline ion distribution. (c) Peak intensity distance pro-

files of theophylline ions (adapted from Kreye et al.,

2012[19]).


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aging

Colloidal carriers for dermal delivery

23

12. Bonnel D, Longuespee R, Franck J et al.: Multivariate ana-

lyses for biomarkers hunting and validation through on-

tissue bottom-up or in-source decay in MALDI-MSI: appli-

cation to prostate cancer. Anal Bioanal Chem, (2011).

13. Brignole-Baudouin F, Desbenoit N, Hamm G et al.: A New

Safety Concern for Glaucoma Treatment Demonstrated

by Mass Spectrometry Imaging of Benzalkonium Chloride

Distribution in the Eye: An Experimental Study in Rabbits.

Plos One, Just accepted (2012).

14. Bunch J, Clench Mr, Richards Ds: Determination of phar-

maceutical compounds in skin by imaging matrix-assisted

laser desorption/ionisation mass spectrometry. Rapid

Commun Mass Spectrom 18(24), 3051-3060 (2004).

15. Sugiura Y, Zaima N, Setou M, Ito S, Yao I: Visualization of

acetylcholine distribution in central nervous system tissue

sections by tandem imaging mass spectrometry. Analyti-

cal and Bioanalytical Chemistry 403(7), 1851-1861 (2012).

16. Earnshaw Cj, Carolan Va, Richards Ds, Clench Mr: Direct

analysis of pharmaceutical tablet formulations using ma-

trix-assisted laser desorption/ionisation mass spectro-

metry imaging. Rapid Commun. Mass Spec. 24(11), 1665-

1672 (2010).

17. Belu Am, Davies Mc, Newton Jm, Patel N: TOF-SIMS Cha-

racterization and Imaging of Controlled-Release Drug

Delivery Systems. Analytical Chemistry 72(22), 5625-5638

(2000).

18. Klerk La, Dankers Pyw, Popa Er et al.: TOF-Secondary Ion

Mass Spectrometry Imaging of Polymeric Scaffolds with

Surrounding Tissue after in Vivo Implantation. Analytical

Chemistry 82(11), 4337-4343 (2012).

19. Kreye F, Hamm G, Karrout Y et al.: MALDI-TOF MS ima-

ging of controlled release implants. Journal of Controlled

Release 161(1), 98-108 (2012).

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


21


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


22



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


23


26

References

1. Callaghan T.M., Wilhelm K.P. A review of ageing and an

examination of clinical methods in the assessment of

ageing skin. Part I: cellular and molecular perspectives of

skin ageing. Int. J. Cosmet. Sci. 2008, 30(5), 313-22.

2. Kaur I.P., Kapila M., Agrawal R. Role of novel delivery sys-

tems in developing topical antioxidants as therapeutics to

combat photoageing. Ageing Res. Rev. 2007, 6, 271-288.

3. Gašperlin M, Gosenca M. Main approaches for delivering

antioxidant vitamins through the skin to prevent skin

ageing. Expert Opin. Drug Deliv. 2011, 8(7), 905-919.

4. Jurkovič P., Šentjurc M, Gašperlin M, et al. Skin protection

against ultraviolet induced free radicals with ascorbyl pal-

mitate in microemulsions. Eur. J. Pharm. Biopharm. 2003,

56, 59-66.

5. Špiclin P., Gašperlin M., Kmetec V. Stability of ascorbyl

palmitate in topical microemulsions. Int. J. Pharm. 2001,

222(2), 271-279.

6. Kristl J., Vovk B., Gašperlin M, et al. Effect of colloidal carri-

ers on ascorbyl palmitate stability. Eur. J. Pharm. Sci. 2003,

19(4), 181-189.

7. Date A.A., Patravale V.B. – Microemulsions: applications in

transdermal and dermal delivery. – Crit. Rev. Ther. Drug

Carrier Syst. 2007, 14, 547-596.

8. Makai M., Csányi E., Németh Z.S., Pálinkás J., Erős I. - Struc-

ture and drug release of lamellar liquid crystals containing

glycerol. – Int. J. Pharm. 2003, 256, 95-107.

9. Lawrence M.J., Rees G.D. – Microemulsion-based media as

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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