APV Focus Group Drug Delivery

APV Focus Group Drug Delivery Combining Science & Technology to Create Advanced Drug Delivery Systems INTERNATIONAL ASSOCIATION FOR PHARMACEUTICAL TECHNOLOGY NEWSLETTER ISSUE 3/2006

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TABLE OF CONTENTS

◊ DRUG DELIVERY EVENTS: Upcoming seminars and conferences ◊ DRUG DELIVERY PRODUCTS: IONSYS™ / Orapred ODT™ ◊ DRUG DELIVERY COMPANIES: In focus: Flamel Technologies Inc. ◊ DRUG DELIVERY TERMINOLOGY: Transmucosal / Mucosal / Sublingual / Buccal (Administration) ◊ DRUG DELIVERY PEOPLE: In focus: Ruth Duncan ◊ FEATURED ARTICLE: PEGylation: Quo vadis? ◊ DRUG DELIVERY LITERATURE: Recently published reviews in the field of drug delivery ◊ ABOUT OUR FOCUS GROUP: Who we are and what we do

DRUG DELIVERY EVENTS BACK TO TABLE OF CONTENTS

Meeting: PolyPharma - Polymers in Pharmacy Details Halle (D), September 24th - 26th, 2006 APV Seminar: Biopharmaceutical Manufacturing Excellence - APIs derived from Microorganisms Details Vienna (A), October 10th - 11th, 2006 Meeting: 2006 AAPS Annual Meeting and Exposition Details San Antonio, TX (USA), October 29th - November 2nd, 2006 APV Seminar: Achievements & Trends in Pulmonary Delivery Details Marburg (D), November 9th, 2006 Suggest a meeting to be announced!

DRUG DELIVERY PRODUCTS BACK TO TABLE OF CONTENTS

IONSYS™ (ALZA Corporation / Ortho-McNeil, Inc./Janssen-Cilag) ALZA received marketing authorization in Jan. 2006 from the EMEA and in May 2006 from the FDA for fentanyl delivered with the E-TRANS® iontophoretic transdermal drug delivery system developed by ALZA, which uses a weak electric current to rapidly deliver fentanyl across the skin and into the bloodstream. IONSYS is indicated for the short-term management of acute post-operative pain in adult patients requiring opioid analgesia during hospitalization. The first needle-free, patient-activated analgesic system to receive marketing authorization, IONSYS will be marketed in the United States by Ortho-McNeil, Inc., and in the European Union by Janssen-Cilag companies, which along with ALZA, are all affiliates of Johnson & Johnson. The E-TRANS version of fentanyl follows the previous development of D-TRANS® fentanyl transdermal patches at ALZA. The patient-operated E-TRANS device is attached either to the upper outer arm or the chest. When pain medi- cation is needed, the patient double-clicks the dosing button, which delivers a pre-programmed, 40mcg dose of fentanyl through the skin. Each dose is delivered over a 10-minute period. Fentanyl is an opioid agonist and a Schedule II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine and oxycodone. The most common side effects associated with IONSYS in clinical trials were nausea, vomiting, headache and pruritus. These were mostly of mild-to-moderate severity. Details...

Orapred ODT™ (CIMA LABS INC. / BioMarin Pharmaceutical Inc. / Alliant Pharmaceuticals, Inc.) Orapred ODT, prednisolone sodium phosphate orally disintegrating tablets, was approved for marketing in the United States in June 2006 by the FDA. BioMarin developed the product based on CIMA’s proprietary OraSolv® drug delivery technology. The first orally disintegrating tablet corticosteroid dosage form available in the U.S., Orapred ODT is expected to be prescribed primarily for acute exacerbations of asthma in children. The product is also used to control severe, persis- tent asthma and to reduce inflammation seen in numerous medical conditions including arthritis and cancer. OraSolv combines taste masked active drug ingredients with a low effervescence system. OraSolv tablets require PakSolv®, CIMA LABS’ proprietary blister packaging system, which protects the effervescent components of the formulation. Alliant began marketing Orapred ODT in North America Aug. 2006. Alliant will pay BioMarin a $2.5 million upfront payment and $15.5 million in milestone payments, which are primarily contingent upon approval and launch of Ora- pred ODT in the United States. Additionally, Alliant will pay BioMarin royalties ranging from 25 percent to 30 percent on net sales of Orapred ODT, net of the royalties owed to CIMA LABS for use of their proprietary, taste-masking oral disintegrating tablet technology used in Orapred ODT. BioMarin will retain commercial rights outside of North Amer- ica. Details... More... More...

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 1 of 8

DRUG DELIVERY COMPANIES BACK TO TABLE OF CONTENTS

Flamel Technologies Inc. (France - Venissieux) is a drug delivery company with expertise in polymer science and biochemistry. The Company is focusing on innovative delivery systems for oral controlled release of small molecules absorbed only in the small intestine and for long acting parenteral delivery of peptides and proteins. The company has several products in preclinical and clinical development.

Flamel Technologies has a strong research department for polymer science (Venissieux, France) and owns a large cGMP pharmaceutical production facility (Pessac, France).

Fact sheet

Founded: 1990

Location: France - Venissieux

Employees: almost 300 (70% in R&D and production)

Ownership: Flamel Technologies (FLML) entered the NASDAQ in 1996

Key technologies: Flamel’s has two technology platforms, the Medusa® technology for parenteral protein and peptide delivery, and the Micropump® technology for oral delivery of small molecules.

Medusa® Flamel’s Medusa technology uses proprietary polymers from naturally occurring amino acids (Leu hydrophobic and Glu hydrophilic) which spontaneously form stable particles in water by self-assembly. Medusa I technology uses block-co-polyaminoacid of leucine and glutamate in the form of nanoparticles (approx 20-30 nm) Medusa II technology uses a hydrophobically modified polyglutamate and can be formulated as nanoparticles (50 nm) or as denser micro particles (5 - 50 µm).

The Medusa technology is a simple aqueous based technology. The resulting particles are claimed to be robust over a wide range of pH values and can be stored as either stable liquid or stable dry forms. The design of the Medusa “polypeptide-like” amino acid polymers allows a non-covalent capture and subsequent delivery of native peptide or protein drugs. Once injected in the body, the particles release the captured drugs in a controlled manner and over an extended period of time (1-4 weeks). Both processes (capture and release) are non- denaturing, which preserves structural integrity - and hence the biological activity - of the drug. This could represent an interesting alternative to chemical modification such as PEGyla- tion or polymer-conjugation.

Micropump® The Micropump technology is based on coated drug micro particles (200-500 µm), manufac- tured by fluidized bed spray coating, which provide an extended oral release up to 20 hours. It can be applied as a controlled release form (Micropump I) and as a delayed and extended release form (Micropump II). The Micropump technology is a multiparticulate system containing a large number of micro particles: 5,000 to 10,000 particles per dose in either a capsule or a tablet form and up to 50,000 in a suspension or sachet. This allows a flexibility with regard to dose and delivery system and makes it suitable for pediatric or geriatric use as well.

The Micropump micro particles are designed in such a way as to retard their transit through the small intestine (by adhesive properties of the particle surface and by the particle sizes leading to entrapment of the particles in the intestinal mucosa). This results in extended plasma mean residence times of drugs, known to be absorbed only in the small intestine, up to about 20 hours, allowing for once-daily dosing without relying on colonic absorption.

Clinical stage Medusa® product pipeline: • Basulin®, a long-acting native insulin for the treatment of type I diabetes. Flamel Technologies published the results of Phase IIa clinical trial on Basulin® beginning of 2005 [Medusa I] • IFN alpha-2b XL, a long-acting native interferon alpha-2b for the treatment of Hepatitis B and C and some cancers. Phase I/II HCV clinical trial completed • IL-2 XL, a second-generation long-acting interleukin-2. Preliminary results of phase I/II trial presented mid 2006 • hGH, a long-acting native human growth h ormone for the treatment of growth disor- ders (preclinical stage) • IFN beta XL, a long-acting interferon beta for the treatment of multiple sclerosis (preclinical stage)

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 2 of 8

Micropump®

• A beta blocker in registration (co-development with GSK) • Genvir™, acyclovir for the treatment of Acute Genital Herpes (in Phase III); Metformin XL, an anti-diabetic for the treatment of type II diabetes (in Phase I)

Website: http://www.flamel.com

Contact: Nigel McWilliam, Director, Business Development, USA Phone: +1 202 862 8400 Fax: +1 202 862 3933 E-mail: [email protected]

DRUG DELIVERY TERMINOLOGY BACK TO TABLE OF CONTENTS

Definitions provided by Karsten Cremer

"TRANSMUCOSAL (ADMINISTRATION)": Administration across a mucosa. Write a comment

The definition is similar to that authorized by the FDA, which has recognized at least 109 modes and/or routes of administration. It should be noted that many modes of systemic administration involve the passage of a drug substance from a composition through a mucosa into the blood circulation, such as peroral, rectal, sublingual, buccal, nasal etc. However, the term is most frequently used for those routes of administration that involve the placement of a liquid, solid, or semisolid pharmaceutical composition onto the mucosa of the oral cavity (i.e. buccal, sublingual, or gingival).

German: "Transmukosale Applikation*" French: Provide a translation Spanish: Provide a translation Suggest a term to be defined ------Suggest a definition

"MUCOSAL (ADMINISTRATION)": Administration onto a mucosa. Write a comment

"Mucosal" is broader than "transmucosal" as it does not require the active ingredient to cross the mucosa. Thus, it covers both systemic and local delivery. Again, the term is most frequently used in the context of the mucosa of the oral cavity.

German: "Mucosale Applikation*" French: Provide a translation Spanish: Provide a translation ------

"SUBLINGUAL (ADMINISTRATION)": Administration across the mucosa beneath the tongue. Write a comment

This definition is more narrow than that authorized by the FDA which does not require transmucosal passage. How- ever, the term is almost exclusively used as in the context of transmucosal delivery.

German: "Sublinguale Applikation*" French: Provide a translation Spanish: Provide a translation ------

"BUCCAL (ADMINISTRATION)": Administration across the mucosa of the cheek. Write a comment

Again, the definition is more specific than that authorized by the FDA which covers all forms of administration di- rected toward the cheek, even though generally from within the mouth.

German: "Bukkale Applikation*" French: Provide a translation Spanish: Provide a translation *Interestingly, many if not most German-speaking colleagues also use the English term "application" rather than the more common (and perhaps somewhat less ambiguous) term "administration".

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 3 of 8

DRUG DELIVERY PEOPLE BACK TO TABLE OF CONTENTS

Ruth Duncan is Professor of Cell Biology and Drug Delivery at the Welsh School of Phar- macy, Cardiff University, UK and Director of the Centre for Polymer Therapeutics.

Duncan completed her PhD studies in 1979 at Keele University and established there the CRC's Polymer-Controlled Drug Delivery Group. In 1992 she joined Farmitalia Carlo Erba (became Pharmacia now Pfizer) in Milan as Head of New Technologies. At this time she was also the Project Team Leader for transfer of two of her own compounds into Phase I clinical trials (the first synthetic polymer-anticancer drug conjugates to be tested clinically). In 1994 she returned to The School of Pharmacy, London where she re-established an interdisciplinary research group called the Centre for Polymer Therapeutics that subsequently relocated to Cardiff in 2000. Her research has now transferred 6 polymer anticancer conjugates into clinical trial and the first 2 polymer-based gamma camera imaging agents.

Her main research interest is the development of Novel Polymer Therapeutics as Nanomedicines, focused on • rationale design based on whole body and cellular pharmacokinetics (endocytosis) • development of polymer anticancer conjugates and their combinations from laboratory to clinic • development of polymeric gamma camera imaging agents from laboratory to clinic

She has contributed more than 300 scientific articles and patents, and has been a recipient of many awards including the Pfizer Research Award for Pharmaceutical Sciences, Young Investigator Award of the Controlled Release Society, Interdisciplinary Award of the Royal Society for Chemistry, the Millennial World Congress Pharmaceutical Scientist Award, the Berlin-Brandenberg Academy of Sciences Monika Knutzner Award for Innovative Cancer Research and was a Princess Takamatsu Cancer Foundation Lecturer in 2004. She is an elected member of the Academy of Sci- ences and Literature Mainz, in 2004 was the Science Chair of the British Pharmaceutical Conference and in 2004/2005 Chaired the Steering Committee of the European Science Foundation's Forward Look on Nanomedicine. Currently Ruth Duncan is a member of the Organizing Committee of the International Symposium on Polymer Thera- peutics 19th - 21st February 2007, Department of Chemistry and Biochemistry, Freie Universität Berlin.

FEATURED ARTICLE BACK TO TABLE OF CONTENTS

PEGYLATION: QUO VADIS?

by Prof. Dr. Gerrit Borchard, Université de Genève, Ecole de Pharmacie Genève-Lausanne, 30, Quai Ernest-Ansermet, CH-1211 Genève

Introduction

PEGylation, the covalent attachment of one or more polyethylene-glycole (PEG) molecules to a protein drug, was invented in the 1970’s, leading to the founding of the first ‘PEGylation company’, Enzon Pharmaceuticals. Besides Enzon, major players in the field of PEGylation today are, among others, Nektar, Mountain View Pharmaceuticals, Celltech (UCB group), Amgen, Roche, Schering-Plough and Eyetech. So far, 7 PEGylated products are in the market (Tab. 1). With the exception of Pfizer/Eyetech’s Macugen, which is a PEGylated aptamer based on an oligonucleotide backbone, all marketed products are proteins.

Tab. 1: Overview of marketed PEG products

Company Product API Indication Amgen Neulasta PEG-GCSF Neutropenia

Enzon Adagen PEG-aminodeaminase Severe Combined Immuno Deficiency (SCID) Enzon Oncaspar PEG-asparaginase Acute Lymphoblastic Leukemia (ALL) Eyetech/Pfizer Macugen PEG-aptanib Age-related Macular Degeneration (AMD) Pfizer Somavert PEG-hGH antagonist Acromegaly Roche PEGasys PEG-interferon-alfa-2a Hepatitis C Schering-Plough PEG-INTRON PEG-interferon-alfa-2b Hepatitis C

PEG and Protein Delivery

The application of therapeutic proteins is facing several challenges, among which are the mandatory application by injection (with few exceptions, e.g., Exubera, inhaled insulin), low enzymatic resistance, rapid renal elimination and

resulting low t1/2 and AUC, and potential immunogenicity. PEGylation is posed to improve on these properties through shielding the protein against immunological recognition and enzymatic attack by steric hindrance, and re- ducing renal filtration by increasing the overall molecular weight, with 40kDa signifying the threshold molecular weight for PEGylated compounds (Fig. 1). Reduction of local irritation or immune reactions at the injection site have also been reported after PEGylation. The observation that PEGylated compounds or delivery systems accumulate preferably in tumor tissues or in joints under inflammatory conditions has caused the group of Maeda et al. (J. Con-

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 4 of 8

trol. Rel. 2000; 65:271) to postulate the enhanced permeation and retention (EPR) effect. Due to the higher permeability of blood ves- sels, PEGylated drugs can better penetrate into these tissues, and due to reduced or absent lymphatic drainage, are not easily elimi- nated. Overall, PEGylation results in a significant increase in retention time of the API in the blood circulation, passive targeting by the EPR effect, reduction of immunological side effects, reduction in application frequency and thus general enhancement of patient compliance and adherence to therapy.

PEG Linker Strategies

However, PEGylation also faces several challenges. Early N- Fig. 1: Renal clearance vs. PEG molecular weight. hydroxysuccinimide chemistries involving attachment of PEG to Adapted from Jorgensen & Moller, Am. J. amino functions did result in random PEGylation. This resulted in Physiol. 1979; 236:130. considerable challenges to production uniformity and quality assur- ance. In addition, PEG sites may be closely located to the reactive or binding site of the protein, which may impair its activity or binding affinity to the API’s receptor. This, however, may not be true in every case, as shown in Tab. 2 for a number of proteins.

While PEG-aldehyde chemistry allowed to target the N-terminus Tab. 2: PEGylation at or near binding domains more specifically by variation of the reaction pH, more advanced may not result in loss in biological activity thiol and maleimide chemistries allowed the specific PEGylation of PEG- Binding Biol. free sulfhydryl moieties. Examples for the strong effect of binding PEG-Site after random or site-specific PEGylation of antibodies and anti- Protein Domain Activity body fragments are given in Tab. 3. PEGylation can lead to a Cys29-Asp35 Lys 31 IFN + reduction of in vitro activity of the modified molecule, which does Phe-123-Trp140 Lys 121,131,134 not necessarily correspond to a loss in biological activity in vivo (Tab. 4). It is thought that biopharmaceuticals may have a higher G-CSF Glu19 Lys 16,23,34,40 + binding affinity to their targets than needed for cellular activity, and that this affinity is only partially reduced by PEGylation Epoietin Sugars Sugars + (Pearce et al., Biochemistry 1999; 38:81). In general, a poor in *Insulin Gly1 Gly1 + vitro/in vivo correlation is observed for PEGylated compounds, making candidate selection processes tedious and time- * Caliceti & Veronese, Proc. Intl. Symp. Control Rel. Bioact. Mat. 27 (2000); Bailon & Ehrlich “Innovative Drug Delivery Systems” consuming. Symposium (2002)

New avenues for permanent PEGylation are being pursued by companies such as Neose and Polytherics. The former has developed technology to glycosylate proteins expressed in E. coli, or optimize glycosylation patterns by specific enzymatic GalNAc glycosylation of serine and threonine. Successively, sialic acid conjugated PEG is enzymatically transferred to these GalNAc residues. The technology has been successfully applied to E. coli expressed G-CSF, interferon-alpha, and GM-CSF (DeFrees et al., Glycobiology, Advance Access May 22, 2006). Comparison of pharmacokinetic data of the thus PEGylated compounds to ‘traditionally’ PEGylated G-CSF revealed a two-fold increased AUC for the glycoPEGylated compound. The company has recently concluded a PEG-erythropoeitin Phase I trial in Europe, and expects to commence Phase II trials in the 4th quarter of 2006. Together with BioGenerix, Neose will also per- form a Phase I trial of their glycoPEG-GCSF in Q3/06 in Europe.

Tab. 3: Random vs specific PEGylation, effect on Ag binding.

Site-Specific Antibody Random PEGylation Ag Binding Effect Reference PEGylation

Hu Anti-Hepatitis B IgG 4xPEG 1.7kDa - 30% Loss Suzuki, 1984

Hu Anti-Hepatitis B IgG 15xPEG 1.7kDa - > 80% Loss Suzuki, 1984

Mu A5B7 F(ab’)2 2xPEG 5kDa - 12% Loss Pedley, 1994

Mu A5B7 DFM (diFab’) 1-2xPEG 25kDa - 40% Loss Casey, 2000

Hu diFab’ 1xPEG 40kDa - 78% Loss Chapman, 2002

Mu A5B7 Fab’ 2xPEG 5kDa - 20% Loss Pedley, 1994

Anti-Tag-72 scFv 1xPEG 20kDa - 40% Loss Lee, 1999

Hu Fab’ 1xPEG-40kDa - 47% Loss Chapman, 2002

Hu Fab’ - 1xPEG 25kDa 107% Retention Chapman, 2002

Hu Fab’ - 2xPEG 25kDa 100% Retention Chapman, 2002

Hu Fab’ - 1xPEG 40kDa 102% Retention Chapman, 2002

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 5 of 8

Another approach is the technology developed at the Imperial College, London (UK), which led to the spin-off of the company PolyTherics. The PEGylation method developed by Polytherics (EP1648518) is performed by reduction of the intramolecular bonds between two sulphur atoms (‘disulfide bridges’) and successive annealing of these bonds by using a spacer molecule, which is itself attached to PEG. The company has performed studies on the PEGylation of interferon alpha-2b (Shaunak et al., Nat. Chem. Biol. 2006; 2:312) and claims that PEGylation cocurs completely site-specific at ‘accessible’ disulfides only, and that the native protein conformation is maintained. Certainly based on a brilliant chemistry, pharmacokinetic, toxicological, and immunogenicity issues, however, have not completely been addressed yet.

Tab. 4: In Vitro vs. In Vivo Activities of Pegylated Biopharmaceuticals

Protein PEG (kDa) In vitro (%) In vivo (%) t1/2 unmodified t1/2 modified human human G-CSF 20 5 977 3.5 16

IFN 2x20 7 - 5.1 168

OB 2x20 10 263 0.4 24

Epoietin 30 NA 650 6.8 27 Bailon & Ehrlich “Innovative Drug Delivery Systems” Symposium, Philadelphia, PA (2002)

Disadvantages of the PEGylation process, such as possible reduction in bioactivity, may be overcome by a new class linkers molecules, binding PEG reversibly to the protein, virtually creating a pro-drug from which the active principle is released by hydrolysis or enzymatic activity over a prolonged period of time (Greenwald et al., J. Med. Chem. 1999; 42:3657). An advantage of this technology, which is considered as the next PEG linker generation, is that the native compound is recovered, and may have better access to compartments within the body than the high molecular weight PEGylated compound. In addition, releasable linkers can be designed to show a certain release profile, or even site-specific cleavage. Greenwald et al. (J. Med. Chem. 2004; 47:726) and Zhao et al. (Bioconjugate Chem. 2006; 17:341) have described the development of the aliphatic releasable bicin 3 (BCN3) linker. This linker was successively used for reversible PEGylation of lysozyme and interferon-beta-1b, resulting in enhanced pharmacokinetics and sustained release of the API in studies in mice. The group of Shechter at the Weizman Institute in Israel has developed another (aromatic) releasable linker (Shechter et al. FEBS Letters 2005; 579:2439). PEG was coupled

through this linker to a variety of APIs, including Y2R receptor agonist PYY3-36, interferon-alpha, exendin-4 and human growth hormone (Peleg-Shuman et al., J. Med. Chem. 2004; 47:4897, Tsubery et al., JBC 2004; 37:38118). In each case, reversible PEGylation resulted in enhanced pharmacokinetics of the native compound.

Summary

Since its inception in the 1970s, PEGylation has matured into a technology that offers the opportunity to improve on the properties of the full spectrum of peptide, protein and oligonucleotide based drugs. Although not a trivial feat, PEGylation using permanent linkers is generally regarded as a commodity. Permanent linker chemistries – useful or not – have been vastly patented, leaving little room for new IP, with the technologies developed by Neose and Poly- therics being among the few exceptions. The development of releasable linker chemistries appears as a step forward, possibly offering the opportunity to create ‘true’ biogenerics, as the API is regenerated from the PEG linkage, regain- ing its specific pharmacokinetic and bioactivity profile. Although a few releasables have been developed, the proof of concept still needs to be shown in the clinic.

In conclusion, the lessons learned in PEGylation technology are: • An ideal PEG reagent is derived from simple, proven, straightforward chemistry that produces linkages at pre- dictable sites, contains non-immunogenic and non-toxic spacers or linkers and produces reaction byproducts that are innocuous. • In vitro activity of PEG products is not predictive of their biological activity. • PEGylation at or near binding domains may not necessarily result in loss of biological activity. • Site-specific PEGylation of antibodies or antibody fragments alleviates loss of antigen binding usually seen for random PEGylation and maintains binding affinity. • Releasable PEGylation offers the opportunity to develop conjugates releasing the original API in a sustained release pattern.

References

Suzuki et al., Biochem. Biophys. Acta 1984; 788:248. Pedley et al., Br. J. Cancer 1994; 70:1126. Casey et al., Tumor Target. 2000; 4:235. Chapman, Adv. Drug Del. Rev. 2002; 54:531. Lee et al., Bioconj. Chem. 1999; 10:973.

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 6 of 8

DRUG DELIVERY LITERATURE BACK TO TABLE OF CONTENTS

RECENTLY PUBLISHED LITERATURE REVIEWS IN THE FIELD OF DRUG DELIVERY

The role of filtration in drug delivery systems. Hogan B. Med Device Technol. 2006 Jun;17(5):22-4.

Emerging use of nanoparticles in diagnosis and treatment of breast cancer. Yezhelyev MV, Gao X, Xing Y, Al-Hajj A, Nie S, O'Regan RM. Lancet Oncol. 2006 Aug;7(8):657-67.

[Drug administration and dosage forms in geriatric patients] Heppner HJ, Sieber CC, Esslinger AS, Trogner J. Ther Umsch. 2006 Jun;63(6):419-22. German.

[Administering drugs to infants, children, and adolescents] Wagner R, Frey OR. Ther Umsch. 2006 Jun;63(6):411-8. German.

Permeation enhancers in the transmucosal delivery of macromolecules. Sharma S, Kulkarni J, Pawar AP. Pharmazie. 2006 Jun;61(6):495-504.

Application of encapsulated cell technology for retinal degenerative diseases. Tao W. Expert Opin Biol Ther. 2006 Jul;6(7):717-26.

Nanoparticle-based diagnosis and therapy. Groneberg DA, Giersig M, Welte T, Pison U. Curr Drug Targets. 2006 Jun;7(6):643-8.

Nanotechnology based drug delivery system(s) for the management of tuberculosis. Pandey R, Khuller GK. Indian J Exp Biol. 2006 May;44(5):357-66.

Advances in psychotropic formulations. Keith S. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):996-1008. Epub 2006 May 6.

The hair follicle and its stem cells as drug delivery targets. Hoffman RM. Expert Opin Drug Deliv. 2006 May;3(3):437-43.

Drug delivery across the blood-brain barrier: Why is it difficult? How to measure and improve it? Su Y, Sinko PJ. Expert Opin Drug Deliv. 2006 May;3(3):419-35.

Drug delivery strategies using polysaccharidic gels. Coviello T, Matricardi P, Alhaique F. Expert Opin Drug Deliv. 2006 May;3(3):395-404.

Controlled-release microchips. Sharma S, Nijdam AJ, Sinha PM, Walczak RJ, Liu X, Cheng MM, Ferrari M. Expert Opin Drug Deliv. 2006 May;3(3):379-94.

Nanoparticle-aptamer bioconjugates for cancer targeting. Farokhzad OC, Karp JM, Langer R. Expert Opin Drug Deliv. 2006 May;3(3):311-24.

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 7 of 8

ABOUT OUR FOCUS GROUP BACK TO TABLE OF CONTENTS

The APV Drug Delivery Focus Group (APV DD) is a section of the APV (Arbeitsgemeinschaft für Phar- mazeutische Verfahrenstechnik e.V. / International Association for Pharmaceutical Technology), a major European society for those sharing a professional interest in pharmaceutical sciences. The Focus Group was established in 2003 in response to the increasing importance of drug delivery within modern pharmaceutics. Read more... Contact us...

COMBINING SCIENCE AND TECHNOLOGY TO CREATE ADVANCED DRUG DELIVERY SYSTEMS

OUR MISSION STATEMENT:

Modern drug delivery research and development is a truly multidisciplinary approach and must combine all relevant scientific, technical, medical and regulatory aspects required for the design, preparation, testing, manufacturing and registration of drug delivery systems and their components. It is the mission of the APV Drug Delivery Working Group to foster and promote all aspects of research and development required to transform drug molecules into safe, applicable and acceptable drug delivery systems, which provide therapeutic benefit, convenience to the patient and improve patient compliance.

Our mission includes in particular the following tasks:

• Thoroughly understanding the physical-chemical and biopharmaceutical properties of the drug substance to be delivered and the components of the drug delivery system • Understanding the biological barriers and the interactions of the drug molecule and its delivery system with the biological environment and the biological target including PK/PD and PK/safety relationships • Research on excipients, materials and technologies required for the design, preparation and manufacturing of drug delivery systems for a selected route of administration • Development and understanding of methods for in vitro and in vivo evaluation of drug delivery systems and their components • Knowledge of regulatory requirements for clinical testing, manufacturing and registration of drug delivery systems

All disciplines relevant to the above mentioned areas of drug delivery R&D are invited to contribute to the APV Drug Delivery Group:

Pharmaceutics, Biopharmaceutics, Analytics, Biology, Physical Chemistry, Biochemistry, Physics, Engi- neering Sciences, Nano Technology, Material Sciences, Polymer Science, Toxicology, Drug Safety, Clinical Research, Drug Regulatory Affairs, etc. Read more...

MEMBERS OF THE APV DRUG DELIVERY FOCUS GROUP

Karsten Cremer, PhD Jeffry L. Grunkemeyer, MBA Gerhard Renner, PhD (Focus Group Leader) Business Development Manager Business Director Technology Founder and Principal Phares Drug Delivery AG, CH-Muttenz Degussa Pharma Polymers, D-Darmstadt Pharma Concepts GmbH, CH-Basel

Rainer Alex, PhD Michael Horstmann, PhD Bernd-Ulrich Riebesehl, PhD Global Coordinator Head of Transdermal and Analytical R&D Research Advisor Pharmaceutical and Analytical R&D LTS Lohmann Therapie-Systeme AG, D-Andernach Lilly Forschung GmbH, D-Hamburg Hoffmann-LaRoche AG, CH-Basel

Johannes Bartholomäus, PhD Karsten Mäder, PhD Jürgen Zirkel, PhD Head of Pharmaceutical Development Professor of Pharmaceutics Managing Director Grünenthal GmbH, D-Aachen Martin-Luther-University, D-Halle/Saale Lipoid GmbH, D-Ludwigshafen

Stefan Bracht, PhD Gerben Moolhuizen, MBA Head of Early Development Business Development Manager and Drug Delivery Systems OctoPlus B.V., NL-Leiden Pharmaceutical Development Schering AG, D-Berlin

Helmut Fricke, PhD Jörg Ogorka, PhD Consultant Head of Life Cycle Management D-Hamburg Novartis Pharma AG, CH-Basel Contact us!

Disclaimer: This newsletter is provided “as is” and without warranty, express or implied. All warranties with regard to the accuracy, reliability, timeliness, usefulness or completeness of the information contained in the news-letter are expressly disclaimed. All implied warranties of merchantability and fitness for a particular use are hereby excluded. None of the information provided in the newsletter constitutes, directly or indirectly, the practice of medicine, the dispensing of medical services, the recommendation to buy or use a product. External links are provided in the newsletter solely as a convenience and not as an endorsement of the content on such third-party websites. The APV Drug Delivery Focus Group is not responsible for the content of linked third-party sites and does not make any representations, warranties or covenants regarding the content or accuracy of materials on such third-party websites. If you decide to access linked third-party websites, you do so at your own risk.

APV Drug Delivery Focus Group Newsletter – 3/2006 Page 8 of 8