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Newsletter Volume 4, Number 1 November 2009 Newsletter Volume 4, Number 1 November 2009 Page 2 Phospholipid Research Center News Meeting of the Scientific Board, October 2, 2008 in Ludwigshafen It should contain the following paragraphs: 1. 2. 3. 4. 5. 6. 7. Introduction Aim Preliminary results Conclusions Future perspectives Publications References Participants: Prof. Alfred Blume (Scientific Board) Prof. Gert Fricker (Scientific Board) Dr. Frank Martin (Scientific Board) Prof. Christel Müller-Goymann (Scientific Board) Dr. Ralf-Olaf Quinkert (Scientific Board) Dr. Herbert Rebmann (PRC) Dr. Constanze Setzer (PRC) Mr. Armin Wendel (PRC) Dr. Jürgen Zirkel (PRC) Announcement of new Managing Director At the last meeting of the Scientific Board in Ludwigshafen, it was decided to support the following submitted research proposals: On October 1st 2009, Dr. Constanze Setzer took over the position as Managing Director of the Phospholipid Research Center. For more information about the funding of projects, please visit our website: www.phospholipids.net. Martin Brandl, University of Southern Denmark: “Oral bioavailability Screening of new Drug Compounds: Comparison of the Phospholipid Vesicle based Model with the Caco-2 Model” (Supplemental funding) To simplify the applications in future, a general form was advised. The proposal (4-5 pages in length) should be divided into the following parts: 1. 2. 3. 4. 5. 6. 7. Abstract Introduction to the topic Aim of the project Methods Work plan Timeline Costs Dr. Setzer holds a Diploma in Chemistry and a Master in Business Administration. She has 15 years of management experience in Research and Development and Technical Customer Service in the chemical industry. An annual report should reveal the progress of the funded project. Phospholipid Forschungszentrum e.V./ Research Center Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 3 Industry News Lipid Therapeutics and Dr. Falk Pharma to develop a new treatment approach to ulcerative colitis Lipid Therapeutics GmbH and Dr. Falk Pharma GmbH announced that they have entered into a co-development and licensing agreement for product LT-02 applied in the treatment of ulcerative colitis. Ulcerative colitis is a disabling inflammation of the lower gut, affecting more than one million people worldwide. Lipid Therapeutics’ LT-02 is a specially formulated phospholipid that augments the natural protective mucosal barrier in the lower gut. With this treatment approach, Lipid Therapeutics has the first program worldwide that targets the pathological changes in the lower gut barrier function of colitis patients, which are thought to be one of the main underlying disease causes. This compelling mechanism of action, which has already demonstrated activity in clinical trials, thus holds great promise for the treatment of this disease. Lipid Therapeutics and Dr. Falk Pharma will jointly develop LT-02 through a phase IIb clinical trial. MediGene reorganizes to focus on clinical programs The German biotechnology company MediGene is restructuring operations to focus on clinical R&D programs. It will close its early-stage research department and redeploy the staff and financial resources to the company's clinical development and manufacturing departments so the measures will involve few redundancies. One of MediGene's two clinical programs is for EndoTAG-1. EndoTAG1 is designed to destroy existing tumor blood vessels, targeting their negatively charged endothelial cells with its cationic carrier liposomes. It is different from anti-angiogenic drugs, which block the formation of new tumor blood vessels. Phospholipid Forschungszentrum e.V./ Research Center The product is in Phase II testing for the treatment of pancreatic cancer and breast cancer and in Phase I for other oncology indications. Transave's liposomal amikacin promising in bronchiectasis Transave currently develops an inhaled liposomal formulation of the aminoglycoside antibiotic amikacin, Arikace. The US company has shown positive results in a Phase II trial in patients with bronchiectasis and pseudomonal lung infections. Amkacin has been widely available for a number of years as an injectable agent for the treatment of susceptible bacterial infections. There is currently no antibiotic specifically approved for the treatment of bronchiectasis or associated lung infections in the US or EU. Compilation of literature: Constanze Setzer Literature Report Formulation and Evaluation of Liposomes of Ketoconazole Patel R.P., Patel H., Baria A.H., International Journal of Drug Delivery Technology 1(1):16-23, 2009. Multilamellar vesicles for topical application encapsulating the antifungal drug Ketoconazole were prepared using soya lecithin. Liposomes were prepared by thin film method and characteristics as well as in vitro release were studied. It was found that drug release from the liposomes primarily depends on the lipid composition, drug to lipid ratio and also the volume of hydration medium. Possible advantages of encapsulation of Ketoconazole into liposomes are Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 4 less side effects and prolonged release of the active. Production of Lipid Microparticles Magnetically Active by a Supercritical Fluid-based Process embodiments, the pharmaceutically active compounds are ansamycins and the overall formulation is substantially devoid of medium and long chain triglycerides. Vezzù, K., Campolmi, C., Bertucco, A., International Journal of Chemical Engineering 2009:1-9. US Pat. Appl. 20090238865; September 24, 2009 Magnetite nanoparticles were coated with mixtures of phospholipids, triestearin and oleic acid to increase their bioavailability. The magnetite particles are manufactured by a technique based on gas saturated solution process working with supercritical CO2.The characteristics of the particles and encapsulation of the magnetite nanoparticles were studied. The process leads to small lipid coated nanoparticles, which can be trapped by an external magnet producing a magnetic field compatible with human application. The invention concerns nanocapsules, in particular with an average size less than 50 nm, consisting of an essentially lipid core liquid or semiliquid at room temperature, coated with an essentially lipid film solid at room temperature having a thickness of 2-10 nm. The invention also concerns a method for preparing same which consists in producing a reverse phase of an aqueous emulsion brought about by several temperature raising and lowering cycles. Said lipid nanocapsules are particularly designed for producing a medicine. US Pat. Appl. 20090258065; October 15, 2009 US Pat. Appl. 20090226525; September 10, 2009 Dermatological compositions avermectin nanocapsules Self-assembling nanoparticle drug delivery system comprising Compositions and nanoemulsions containing lipid nanocapsules dispersed in a hydrophilic phase, such nanocapsules including at least one avermectin compound, are useful for the treatment of dermatological pathologies, e.g., rosacea. US Pat. Appl. 20090238880; September 24, 2009 Phospholipid-based pharmaceutical formulations and methods for producing and using same Pharmaceutical formulations and methods of producing and using the same are described and claimed. The formulations are dispersions of phospholipids and one or more pharmacologically active compounds, pharmaceutically acceptable salts thereof, or prodrugs thereof. In specific Phospholipid Forschungszentrum e.V./ Research Center Lipid nanocapsules, preparation process and use as medicine A self-assembling nanoparticle drug delivery system for the delivery of various bioactive agents including peptides, proteins, nucleic acids or synthetic chemical drugs is provided. The self-assembling nanoparticle drug delivery system described herein includes viral capsid proteins, such as Hepatitis B Virus core protein, encapsulating the bioactive agent, a lipid layer or lipid/cholesterol layer coat and targeting or facilitating molecules anchored in the lipid layer. A method for construction of the self-assembling nanoparticle drug delivery system is also provided. Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 5 US Pat. Appl. 20090226509; September 10, 2009 Composition disorders for treatment of inflammatory A pharmaceutical composition for parenteral administration, comprising liposomes composed of non-charged vesicle-forming lipids, optionally including not more than five (5) mole percent of charged vesicle-forming lipids, the liposomes having a selected mean particle diameter in the size range between about 40-200 nm and containing a water soluble corticosteroid for the site-specific treatment of inflammatory disorders, is provided. Compilation of literature: Torsten Kromp Conference Report First Symposium on “Phospholipids in Pharmaceutical Research” on May 10-11, 2009 in Heidelberg, Germany. On May 10-11, 2009, the 1st Symposium on Phospholipids in Pharmaceutical Research took place at the TP Conference Center Technologiepark Heidelberg, Germany. The aim of the meeting was to provide a platform for discussion and contact throughout the spectra of interest of phospholipid scientists. Following the address of welcome by Dr. Herbert Rebmann, the Chairman of the Phospholipid Research Center, Prof. Christel Müller-Goymann, Braunschweig, a member of the Scientific Board of the Phospholipid Research Center and one of the organizers, opened the scientific program. The latter consisted of 15 presentations and more than 50 posters covering many different aspects such as production and analysis of phospholipids, their Phospholipid Forschungszentrum e.V./ Research Center physical properties and the experience with their use in pharmaceutical products as useful additives. The poster session took place in the morning of the second day of the meeting. Three oral presentations dealt with research subjects that were part of projects funded by the Phospholipid Research Center. One, entitled: Tetraether Lipid based Liposomes as oral Drug Delivery System. “, was given by Prof. Gert Fricker, Heidelberg. Prof. Natasa Skalko-Basnet, Tromsø reported on the recent results of her research study focused on “Phospholipid-based Delivery Systems for Phytochemicals”. The third talk given by Dr. Mona Tawab covered “Drug-PhospholipidComplexes: Their pharmaceutical Relevance and structural Properties. The Phospholipid Research Center presented one poster of a funded project. It was together with Prof. Fricker, Heidelberg, about the “Oral Bioavailability of pharmaceutical Actives by NanoSolve”. In addition three posters were presented that introduced research projects funded by the Phospholipid Research Center. One poster was from Dr. Peters, Freiburg, about the project “Phosphatidylcholines in Anticancer Drug Delivery: Mere innocent Bystanders?” Another introduced latest findings in the project “Oral Bioavailability Screening: Comparison of the Phospholipid Vesicle-based Permeation Barrier with Caco-2 Cells”. It was presented by Sarah Fischer, Heidelberg. The third poster by Jan Hüsch dealt with “DrugPhospholipid-Complexes: Their pharmaceutical Relevance and structural Properties.” A reception as well as the conference dinner took place in the Castle of Heidelberg. Italian as well as regional delicacies were served. The 130 participants from all over the world perceived the meeting as informative in a relaxed Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 6 atmosphere. A number of fruitful discussions took place after the oral presentations as well as during the poster session and the breaks. The pleasant social program with the guided tour through the Castle of Heidelberg was well received by the participants. Lysopholipids occur in almost every biological membrane in mammalians. In living cells, LPL results from membrane phospholipids through the enzymatic action of a phospholipase A2 (PLA2), which cleaves the fatty acid from the 2-position of the glycerol backbone. In blood, LPL is generated by PLA2 or by the lecithin-cholesterol-acyl-transferase (LCAT) from phospholipids present in lipoproteins. LCAT transfers a fatty acid from phosphatidylcholine (PC) to cholesterol, which results in a cholesterolester and lysophosphatidylcholine (LPC).i The audience from all over the world during the lectures. Constanze Setzer Information about a special Phospholipid Lysophosphatidylcholine Lysophospholipids (LPLs) are phospholipids that are missing one of their two O-acyl chains. They have a 3-carbon glycerol (or –sphingoid) backbone on which a single carbonyl chain of varied length and saturation is attached. One prominent LPL is lysophosphatidylcholine (LPC). As already mentioned, lysophosphatidylcholine is a naturally occurring component in lecithin and phospholipids. It is produced by enzymatic cleavage of phosphatidylcholine by phospholipase A2. Furthermore, it can result from spontaneous hydrolysis of phosphatidylcholine during manufacturing or storage. Pure lysophosphatidylcholine is a white powder that is soluble in ethanol and dispersable in water. Compared to phosphatidylcholine, lysophosphatidylcholine has increased solubility in water and, in blends with other phospholipids, greater emulsifying activity for the formation of oil-in-water emulsions. Lysophosphatidylcholine, like LPLs in general, can affect fundamental cellular functions, i. e. proliferation, differentiation, survival, migration, adhesion, invasion and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity and carcinogenesis. It accumulates in pathological tissues e. g. in the ischemic myocardium and artheriosclerotic aortas and is participating in inflammation processes. Recently, a novel lipid complex to improve oral delivery of drugs was developed. The lipid com- Phospholipid Forschungszentrum e.V./ Research Center Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 7 plex, which is called LYM-X-SORB, is a highly organized lipid matrix which consists of lysophosphatidylcholine, monoglyceride and fatty acid. It was shown to improve the oral delivery of Fenretinide (N-(4-hydroxyphenyl) retinamide) in mice up to 4-fold in plasma and up to 7-fold in tissue, compared to conventional delivery. Lysophosphatidylcholine, like LPLs in general, was also proven as adsorption enhancers for nasal administration of drugs. The Food and Drugs Administration (FDA) in the USA classified lysophosphatidylcholine and LPLs in general as GRAS (generally recognized as safe) in human food. LPLs were tested for skin tolerance and it was concluded, that they can be declared of safe as cosmetic agent Constanze Setzer Analytical Column HPLC in Phospholipid Analytics HPLC (High Performance Liquid Chromatography) is a widely used technique for separation of chemical substances from nearly every field of chemistry, pharmaceutics and life sciences. Although there are many preparative applications of liquid chromatography, which are also relevant for phospholipids, in this column the analytical side of HPLC will be illustrated. Basically, there are two different phase systems in liquid chromatography, the normal and the reversed phase system. In normal phase systems the packing material of the column, the so-called stationary phase, consists of highly porous material with a polar surface, usually a silica gel. The secPhospholipid Forschungszentrum e.V./ Research Center ond part of the system, the liquid phase, consists of a non polar solvent with variable amounts of a polar modifier. Depending on the polarity of the compounds to separate, typical mobile phases are hexane/ethyl acetate, hexane/2-propanol, chloroform/methanol etc. The retention time of a specific analyte is now dependent form the partition of the analyte between the stationary and the mobile phase. The more polar the analyte, the longer is the retention time. The reversed phase system works by the same principles, though the phases show opposite behavior with respect to polarity of the analytes. As stationary phase usually a silica gel is used, which surface is modified by chemically bonding a nonpolar moiety. In most cases a C8 or C18 hydrocarbon chain is used. Such a modified surface is highly hydrophobic in contrast to the hydrophilic surface of the unmodified silica gel. The mobile phase consists of a polar component, usually water and an organic modifier, often methanol or acetonitril. The higher the content of the organic modifier, the shorter is the retention time of the analyte. In the case of phospholipids these two different phase systems allow for the performance of two different separation tasks. By using the normal phase set up, separation behavior is dominated by the polarity of the phospholipids. Hence, the polar head group of a phospholipid has the major impact on the retention characteristics. The non polar hydrocarbon chains of the fatty acids, bound to the polar head group, show nearly no effect on retention time. This is a big advantage for the analysis of phospholipids from natural sources. An example is the characterization of the PC content in lecithin, which requires a method that separates PC from PE, lyso-PC, Sphingomyelin etc. but does not separate the PC species that differ in the fatty acid pattern only. Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 8 Analyzing phospholipids under reversed phase conditions show totally different chromatograms. The polar head group is also important for the retention behavior. However, in this case the nonpolar hydrocarbon chains of the fatty acids show an important effect on retention. Apart from the length of the hydrocarbon chains, the number of double bonds has an impact on the retention time of a specific phospholipid. Hence, HPLC analysis of phospholipids from natural sources shows rather complex chromatograms with many overlapping peaks. Besides the phase system, the choice of the detector plays an important role in HPLC analysis of phospholipids. The most commonly used detector in HPLC is the UV or UV-VIS detector. It uses the absorption characteristics of the analyte at a specific wavelength. To select an optimal wavelength two aspects have to be considered. Firstly, the UVor UV-VIS spectrum of the analyte should show an absorption band with a high absorption coefficient. Secondly, the mobile phase should exhibit absorption as low as possible at this specific wavelength. This implies for phospholipids that UV detection is limited to the region below 230 nm and to mobile phases such as water, acetonitrile and methanol respectively, which are usually applied under reversed phase conditions. Additionally, due to low absorption coefficients, the sensitivity of UV detection is rather low for phospholipids. ammonia, tri-ethylamine etc. The second requirement can be met easily as phospholipids have sufficiently high molecular masses. Consequently, the ELSD should be the ideal detector for phospholipids, however, there are some disadvantages too. Although the sensitivity is better than for UV detectors, it is often difficult to detect small amounts of by-products with a concentration of less than 0.5 %. In this cases thin layer chromatography is still the method of choice, because it is reliable and fast. A second disadvantage is due to the measuring principle. Especially for low concentrations, there is no linear relation between the amount of analyte and the detector signal. A third detector with a fast growing importance is the mass spectrometer. Since the development of efficient coupling techniques between HPLC and mass spectrometry it becomes more and more important, especially for the detection of trace amounts of contaminants and for structure determination. In one of the next “analytical columns” a more detailed review on phospholipids and mass spectroscopy will be provided. Ralf-Olaf Quinkert An often used alternative to the UV-detector for the detection of Phospholipds and other substance with low UV absorption is the Evaporative Light Scattering Detector (ELSD). Principle requirements are a mobile phase which is completely volatile and an analyte which is not volatile. The first requirement excludes the use of phosphoric acid and its salts for adjusting pH, but in most cases it can be substituted by other buffering substances such as acetic acid, formic acid, tri-fluoro acetic acid, Phospholipid Forschungszentrum e.V./ Research Center Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net Newsletter Volume 4, Number 1 November 2009 Page 9 Contact Phospholipid Research Center Im Neuenheimer Feld 582 69120 Heidelberg Germany Phone: +49 (0)6221 / 588 8360 Fax: +49 (0)6221 / 651 5665 E-Mail: [email protected] Web: www.phospholipids.net 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 newsletter are expressly disclaimed. All implied warranties of merchantability and fitness for a particular use are herby 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 Phospholipid Research Center is not responsible for the content of linked third-party websites 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. Phospholipid Forschungszentrum e.V./ Research Center Im Neuenheimer Feld 582 D-69120 Heidelberg VR 3192 Phone +49 (0) 6221 / 588 8360 Fax +49 (0) 6221 / 651 5665 www.phospholipids.net