Liposomal Formulation of Drugs

Polymun′s efficient production technology and know-how ensures sound solutions for a wide range of substances. In many cases a liposomal formulation will clearly improve the efficacy of your drug. Industrial applicability is the focus throughout each project.

Polymun offers the development of liposomal formulations for all kinds of pharmaceutically active ingredients and vaccine antigens. A broad spectrum of analytical methods has been established for this purpose. Polymun produces GMP-material including all necessary documentation for an IMPD. We also assist in planning and implementation of clinical trials. Finally, license agreements are offered for the respective substance on an exclusive basis. Contracts can be arranged step by step - proof of concept, in-depth analysis, GMP-material production, product license - or all in one.

Different encapsulation techniques are employed, depending on the nature of the drug. Hydrophilic substances are passively entrapped. An excellent example is Polymun′s liposomal SOD, which also demonstrates that the liposomal formulation of a known substance can lead to new IP-rights. Amphiphilic substances are actively loaded and hydrophobic drugs or membrane proteins are incorporated into the membrane of the liposomes. The patented liposome production technology is the key to a high quality solution for a broad range of active ingredients used for pharmaceutical or cosmetic application.

Polymun procures special drug delivery compounds from Merck & Cie. Dr. Michael Platscher Custom Synthesis & Services Im Laternenacker 5, CH-8200 Schaffhausen T+41 52 63 07 272, F+41 52 63 07 255 info@merckdrugdelivery.com

Wittycell SAS has contracted Polymun for process development and GMP production of one of Wittycell's proprietary adjuvants.

In 2010, Dafra Pharma Research and Development bvba contracted Polymun with the process development and GMP production of oleylphosphocholine liposomes for the treatment of leishmaniasis in humans.

AC Immune has contracted Polymun for developing a GMP-compliant manufacturing process of AC Immune's Alzheimer's disease vaccine ACI-24. Meanwhile, GMP material was manufactured successfully and is used in a first clinical study in Europe.

In 2008, Polymun has entered into an agreement with Merck Serono for the development of a liposomal cancer vaccine applying Polymun's proprietary liposome manufacturing technology.

Polymun is partner in the project EuroNeut-41 within the EU 7th Framework Program which started in 2008. This project coordinated by Dr. Raphaelle El-Habib from Sanofi Pasteur is aiming to obtain new HIV vaccines inducing neutralizing antibodies. Polymun is contributing its liposome technology to formulate gp41 derived antigens and to manufacture GMP-compliant material for clinical studies.

In September 2007, an agreement was signed with Sign Path Pharmaceuticals, Inc., USA, for the process development and GMP-compliant manufacturing of a liposomal formulation of curcumin.

In May 2007, Polymun has entered into a Supply Agreement with the US based company ProNAi Inc. . Under the terms of the agreement, Polymun will use its proprietary technology to manufacture ProNAi's drug candidate, which is currently in the final stages of preclinical toxicology testing. ProNAi has submitted PNT2258 as an Investigational New Drug to the federal Food and Drug Administration successfully.

In October 2005, Polymun has entered into a co-operation with novosom AG for the production of GMP-compliant material of novosom's Smarticles®. In January 2006, the co-operation was expanded to Micromethason, novosom's micro dose liposomal glucocorticoid.

In February 2005, Polymun signed a license agreement with Sanochemia Pharmazeutika AG about the liposomal formulation of galantamine for the treatment of neuropathic pain. A clinical phase I/IIa study was performed in 2005/06.

Polymun has coordinated the EU-project (STREP) "Development of a New Vaccine Against HIV: Virosomes Incorporating HIV Proteins" which started in January 2005 and ended in December 2007. In cooperation with the European Molecular Biology Laboratory (Grenoble, France) the Biomedical Primate Research Centre (Rijswijk, Netherlands) and the Institute of Applied Microbiology (Vienna, Austria) our liposome technology was used to produce virosomes with recombinant gp41 and proteins from viral lysates.

Advantages of liposomal formulation:

Protection
Liposomes shield the drug from external degradation caused e.g. by oxidation or chemical reactions. This can facilitate the storage of the substance. In the body liposomes prolong the biological half-life. Our liposome preparations themselves are stable over more than tree years at room temperature. Stability will only be limited by the drug itself. This enables to store two components together when packed before separately in liposomes. In addition, liposomes can enhance the solubility within the aqueous core and the lipid membrane.

Transport
Liposomes allow transport in and through the skin. Inhaled they reach the lung. But also more unusual routes can be taken such as transport through the tympanic membrane.

Non-Invasive Application
Liposomal preparations can be applied to target the skin and the tissue below. The mucosa is an excellent target for quick uptake of liposomal drug formulations. Alternatively, liposomes can be inhaled in order to target the lung using appropriate nebulizers.

Sustained Release
Liposomes constitute a drug depot. The release is stretched over a long period in a constant way when compared to the application of the plain drug. Consequently, undesired peak concentrations are avoided and the bio-availability is prolonged. A lower frequency of application and the reduction of side effects are achieved. Such depots can be formed in the skin for the surrounding tissue or in the lung for the blood stream.

Low Application Dose
Confining the distribution of the drug only to the actual target in the body and avoiding peak concentrations by sustained release results in a high reduction of needed drug. This prevents negative side effects and economizes your product.

Toxicity Minimization
In cancer treatment liposomal formulations are used for reducing the toxic side effects of the drug.

Meet us at:

CPhI 2011, October 25-27 2011, Frankfurt, Germany: Dr. Dietmar Katinger

Patents:

Method and device for producing lipid vesicles
granted by: AU 2002215987; CA 2,427,640; EP 1 337 322 (AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR); US 6,843,942

Application of superoxide dismutase in liposomes
granted by: AU 690377; CA 2,204,493; EP 0 789 584 (AT BE CH/LI DE ES FR GB IE IT PT); MX 206295; NZ 296098; US 5,942,245; US 6,312,720

Superloaded liposomes for drug delivery
granted by: EA 200602172; CN 1960706A
pending in: : AU, CA, EP, IN, JP, KR, US, international stage WO2005115337

Liposomal composition comprising an active ingredient for relaxing smooth muscle production and therapeutically use of said composition
granted by: AU 04024753.8, EA 011391; NZ 554183
pending in: CA, CN, EP, IN, JP, KR, US, international stage WO2006042701

Publications:

Vorauer-Uhl K, Jeschek D, Lhota G, Hahn R, Wagner A, Katinger D (2011) Impact of Alcoholic Solvents on the Recovery of Phospholipids in HPLC Analysis. Journal of Liquid Chromatography & Related Technologies 34(3):217-30

Wagner A, Vorauer-Uhl K (2011) Liposome Technology for Industrial Purposes. Journal of Drug Delivery 2011, 9 pages

Vorauer-Uhl K, Jeschek D, Lhota G, Wagner A, Strobach S, Katinger H (2009) Simultaneous Quantification of Complex Phospholipid Compositions Containing Monophosphoryl Lipid-A by RP-HPLC. J Liq Chromatogr Rel Technol 32(15):2203-15

Kaipel M, Wagner A, Wassermann E, Vorauer-Uhl K, Kellner R, Redl H, Katinger H, Ullrich R (2008) Increased Biological Half-Life of Aerosolized Liposomal Recombinant Human Cu/Zn Superoxide Dismutase in Pigs. J Aerosol Med Pulm Drug Deliv 21(3):281-90

Reisinger H, Sevcsik E, Vorauer-Uhl K, Lohner K, Katinger H, Kunert R (2007) Serum-free transfection of CHO-cells with tailor-made unilamellar vesicles. Cytotechnology 54(3):157-68

Wagner A, Stiegler G, Vorauer-Uhl K, Katinger H, Quendler H, Hinz A, Weissenhorn W (2007) One Step Membrane Incorporation of Viral Antigens as a Vaccine Candidate Against HIV. J Liposome Res 17(3):139-54

Wild T, Budzanowski A, Vcelar B, Wagner A, Vorauer-Uhl K, Katinger H (2006) Successful treatment of a leg ulcer occurring in a rheumatoid arthritis patient under methotrexate therapy by reduction of oxidative stress and nutritional supplementation, Journal of Wound Healing 5/06:258-61

Wagner A, Platzgummer M, Kreismayr G, Quendler H, Stiegler G, Ferko B, Vecera G, Vorauer-Uhl K, Katinger H (2006) GMP Production of Liposomes-A New Industrial Approach. J Liposome Res 16(3):311-9

Wagner A, Vorauer-Uhl K, Katinger H (2006) Nebulization of liposomal rh-Cu/Zn-SOD with a novel vibrating membrane nebulizer. J Liposome Res 16(2):113-25

Braun E, Wagner A, Fürnschlief E, Katinger H, Vorauer-Uhl K (2005) Experimental design for in vitro skin penetration study of liposomal superoxide dismutase. J Pharm Biomed Anal 40(5):1187-97

Riedl CR, Sternig P, Galle G, Langmann F, Vcelar B, Vorauer K, Wagner A, Katinger H, Pflüger H (2005) Liposomal Recombinant Human Superoxide Dismutase for the Treatment of Peyronie′s Disease: A Randomized Placebo-Controlled Double-Blind Prospective Clinical Study. Eur Urol 48(4):656-61

Lenz O, Dittmar MT, Wagner A, Ferko B, Vorauer-Uhl K, Stiegler G, Weissenhorn W (2005) Trimeric membrane anchored gp41 inhibits HIV membrane fusion. J Biol Chem 280(6):4095-101

Vorauer-Uhl K, Wagner A, Katinger H (2003) Large Scale Produktion von Liposomen als typische Vertreter partikulärer Trägersysteme. Chemie Ingenieur Technik 75:619-23

Fürnschlief E, Vorauer-Uhl K, Wagner A, Ferko B, Katinger H (2002) Sofortbehandlung von Verbrühungswunden mit liposomal inkorporierter Superoxid-dismutase in der frühen Nachbrennphase. Published in: Kosmetische Medizin, June edition

Vorauer-Uhl K, Wagner A, Borth N, Katinger H (2002) Long term stability of rh-Cu/Zn-SOD-liposomes prepared by the crossflow injection technique following ICH-guidelines. European Journal of Pharmaceutics and Biopharmaceutics 54:77-81

Vorauer-Uhl K, Fürnschlief E, Wagner A, Ferko B, Katinger H (2002) Reepithelization of experimental scalds effected by topically applied superoxide dismutase: controlled animal studies. Wound Repair and Regeneration 10(6):366-71

Wagner A, Vorauer-Uhl K, Kreismayr G, Katinger H (2002) Enhanced protein loading into liposomes by the multiple injection technique. Journal of Liposome Research 12(3):271-83

Wagner A, Vorauer-Uhl K, Kreismayr G, Katinger H (2002) The crossflow injection technique - an improvement of the ethanol injection method. Journal of Liposome Research 12(3):259-70

Wagner A, Vorauer-Uhl K, Katinger H (2002) Liposome produced in a pilot scale: production, purification an defficiency aspects. European Journal of Pharmaceutics and Biopharmaceutics 54:213-9

Riedl CR, Plas E, Vorauer K, Vcelar B, Wagner A, Pflüger H (2001) Pilot study on liposomal recombinant superoxide dismutase for the treatment of Peyronie's disease. Eur Urol 40(3):343-8

Vorauer-Uhl K, Fürnschlief E, Wagner A, Ferko B, Katinger H (2001) Topically applied liposome encapsulated superoxide dismutase reduces postburn wound size and edema formation. European Journal of Pharmaceutical Sciences 14(1):63-7

Vorauer-Uhl K, Wagner A, Borth N, Katinger H (2000) Determination of liposome size distribution by flow cytometry. Cytometry 39(2):166-71