Prof. Dr. Kreuter
a) Research activities
The research activities of the group of Prof. Kreuter are focussed on nanoparticles, liposomes, skin permeation studies and transdermal delivery, haze formation in parenterals, polymeric devices, and stability of dosage forms.
b) Teaching activities
• Three semester lecture and a one semester lab course in pharmaceutics.
• Seminar on pharmaceutical technological analytic methods.
• Seminar about the requirements of the pharmacopea on the manufacturing of pharmaceutical dose forms.
a) Most relevant results achieved in the past
The main research interest of the group of Prof. Kreuter is centered around nanoparticles. Nanoparticles are defined as solid colloidal particles ranging in size from10 nm to 1000 nm (1 µm). They consist of macromolecular materials in which the active principle (drug or biologically active material) is dissolved, entrapped, or encapsulated, and / or to which the active principle is adsorbed or attached. The body distribution of the nanoparticles after intravenous injection was shown tomainly depend on the surface properties of the particles. After injection of these particles into the blood stream, certain blood components (opsonins) are rapidly adsorbed. This adsorption of opsonins leads to a rapid phagocytotic or endocytotic uptake into cells of the reticuloendothelial system (RES), especially into the liver (60 - 90 % ), spleen (2 - 20 %), bone marrow (0.1 - 1 %), and a varying amount into the lungs. Inactivation of opsonins adsorbed in vitro on to the particles prior to injection or adsorption of surfactants reduced the uptake by the RES, and led to a prolongation of the blood circulation time and to an enhanced accumulation in organsand tissues not belonging to the RES. Two lead substances were identified: Poloxamer 1508 is the lead substance to prolong blood circulation time and polysorbate 80 enhances accumulation in organs that do not belong to the RES. Nanoparticles were shown to increase the delivery of anticancer drugs such as mitoxantrone to solid tumors, whereas liposomes led to an enhaned delivery to leucemia cells. The enhanced delivery of this drug to the respective tumors was correlated with an increased antitumoral efficacy.
Nanoparticles coated with polysorbate 80 were endocytosed in vitro and in vivo by brain blood vessel endothelial cells and enabled a peptide, dalargin, to pass through the blood-brain- barrier after intravenous injection. Nanoparticles also were investigated as drug delivery systems for ophthalmic and peroral administration. Pilocarpine nanoparticles prolonged the reduction of the intraocular pressure very significantly in comparison to the aqueous solution of this drug after ophthalmological administration. After peroral administration the nanoparticles mainly accumulated in the Peyer`s patches and M-cells in the intestine and very significantly enhanced the bioavailability of the poorly water soluble drug avarol.
A second research area of this group was the investigation of the skin absorption and permeation of peptides and model permeants. It was established that the skin permeability of amino acids and small peptides is very low. In contrast to most other permeants the absorption pathway of these compounds is through aqueous pores or areas in the skin. Absorption promoters lead to a very long lasting increase in the skin permeability. However, their influence on peptide permeability through human skin is very low, whereas that of iontophoresis is much larger.
The third research area represented the investigation of the reason for the frequently occurring haze formation in parenteral powders after their reconstitution. It was established that the haze was the result of volatile substances such as residual solvents from the polymerization process, residual rubber oligomers, and stabilizers that evaporated from the rubber stoppers during storage of the parenteral powders in vials. These volatiles adsorbed on the powder surfaces and after addition of water for injection formed a hydrophobic colloid. Optimized stoppers with almost no tendency for haze formation were formulated by the industry as a result of our research.
Other research of Prof. Kreuter`s group included polymeric devices such as artifical heart valves and fleces for wound healing.
b) Ongoing research projects
The present research of the group of Prof. Kreuter on nanoparticles focusses on five aspects:
1. Development of nanoparticles made of other polymers (polylactic acid and new polyacrylic acid derivatives for the preparation of surface-functionalized nanoparticles).
2. Investigation of nanoparticles as carriers for antiviral drugs for the treatment of AIDS.
3. Targeting of drugs to the brain.
4. Peroral application.
5. Use of nanoparticles as carriers for oligonucleotides.
In the classical pharmaceutical area ongoing research deals with drug stability investigations for a variety of solid dosage forms by isothermal heat conduction microcalorimetry.
Bundesministerium für Forschung und Technologie
Deutscher Akademischer Austauschdienst
German Israelian Research Foundation
Hessisches Ministerium für Wissenschaft und Kunst
Hoechst AG, Frankfurt/Main
Lohmann Therapie Systeme GmbH, Andernach
3M Medica, Borken/Westf.
Merck AG, Darmstadt
Merz + Co. GmbH, Frankfurt/Main
Rhone-Poulenc Rorer, Paris
Stada AG, Dortelweil
Most relevant publications
Most relevant publications
- Scherer, D., Mooren, F.C., Kinne, R.K.H., and Kreuter, J. (1993); In-vitro permeability of PBCA nanopoarticles through porcine small intestine. J. Drug Target. 1, 21-27.
- Borchard, G. and Kreuter, J.(1993); Interaction of serum components with poly(methylmethacrylate) nanoparticles and the resulting body distribution after intravenous injection in rats. J. Drug Target. 1, 15-19.
- Stieneker, F., Kreuter, J., and Löwer, J. (1993); Different kinetics of the humoral immune response to inactivated HIV-1 and HIV-2 in mice: Modulation by PMMA nanoparticle adjuvant. Vaccine Res. 2, 111-118.
- Schäfer, V., v. Briesen, H., Rübsamen-Waigmann, H., Steffan, A.M., Royer, C., and Kreuter, J. (1994); Phagocytosis and degradation of human serum albumin microspheres and nanoparticles in human macrophages. J. Microencapsul. 11, 261-269.
- Ruland, A., Kreuter, J., and Rytting, J.H. (1994); Transdermal delivery of the tetrapeptide Hisetal (melanotropin (6-9)). II. Effect of various penetration enhancers. In vitro study across human skin. Int. J. Pharm. 103, 77-80.
- Beck, P.H., Kreuter, J., Müller, W.E.G., and Schatton, W. (1994); Improved peroral delivery of avarol with polybutylcyanoacrylate nanoparticles. Europ. J. Pharm. Biopharm. 40, 134-137.
- Berscht, P.C., Nies, B., Liebendörfer, A., and Kreuter, J. (1994); Incorporation of basic fibroblast growth factor into methylpyrrolidone chitosan fleeces and determination of the in vitro release characteristics. Biomater. 15, 593-600.
- Ruland, A., Rohr, U., and Kreuter, J. (1994); Transdermal delivery of the tetrapeptide Hisetal (melanotropin (6-9)) and amino acids: their contribution to the elucidation of the existence of an "aqueous pore" pathway. Int. J. Pharm. 107, 23-28.
- Rössler, B., Kreuter, J., and Ross, G. (1994); Effect of collagen microparticles on the stability of retinol and its absorption into hairless mouse skin in vitro. Pharmazie 49, 175-179.
- Zimmer, A. K., Maincent, P., Thouvenot, P., and Kreuter, J. (1994); Hydrocortisone delivery to healthy and inflamed eyes using a micellar polysorbate 80 solution or albumin nanoparticles. Int. Pharm. 110, 211-222.
- Kreuter, J. (1994); Nanoparticles. in Kreuter, J. (Ed.), (1994); Colloidal Drug Delivery Systems. M. Dekker, New York, 219-342.
- Borchard, G., Audus, K.L., Shi, F., and Kreuter, J. (1994); Uptake of surfactant- coated poly (methyl methacrylate)-nanoparticles by bovine brain microvessel endothelial cell monolayers. Int. J. Pharm. 110, 29-35.
- Cimbollek, M., Nies, B., Liebendörfer, A., Wenz, R., and Kreuter, J. (1995); The potential of the prodrug clindamycin palmitate as an implantable slow release form of the antibiotic clindamycin for heart valves. J. Controlled Rel. 33, 47-53.
- Kreuter, J., Alyautdin, R.N., Kharkevich, D.A., and Ivanov, A. A. (1995); Passage of peptides through the blood-brain barrier with colloidal particles (nanoparticles). Brain Res. 674, 171-174.
Titles of dissertations
Titles of dissertations
- Monika Cimbollek, 1994
Entwicklung einer antibiotikageschützten künstlichen Herzklappe zur Prophylaxe und Therapie der künstlichen Endocarditis
- Petra Carola Eichhorn, 1994
Freigabe von basic Fibroblast-Growth-Factor aus resorbierbaren Trägern zur Förderung der Wundheilung
- Klaus-Dieter Gothier, 1995
Beeinflussung der therapeutischen Wirksamkeit von Antibiotika gegen intraphagozytäre Keime durch Bindung an Nanopartikeln aus Poly- (butylcyanoacrylat)
- Frederique Barbara Landry, 1995
Degradatation of Poly(D,L-Lactic Acid) Nanoparticles in Artificial Gastric and Intestinal Fluids; in vivo Uptake of the Nanoparticles and of their Degradation Products
- Klaus Langer, 1996
Entwicklung und Charakterisierung kolloidaler Systeme als Träger für Muscarinrezeptor-Agonisten zur Anwendung am Auge
- Raimar Löbenberg, 1996
Nanopartikel als Träger für Azidothymidin (AZT)
- Cornelia Marburger, 1996
Polyacrylat-Nanopartikel: Molekulargewichtsbestimmung, Mechanismus und Kinetik radikalischer Polymerisationsreaktionen
- Andreas Rolf Bender, 1996
Nanopartikel und Liposomen als Trägersysteme für antivirale Wirkstoffe gegen HIV: Entwicklung und präklinische Testung in der Zellkultur
- Achim Berthold, 1997
Chitosanmikropartikel: Wirkstoffträger für sterodiale Antiphlogistika
- Frank Hoffmann, 1998
Entwicklung und Evaluierung kolloidaler Wirkstoff-Trägersysteme zur Anwendung bei Herpes-Virus-Infektionen des Auges
- Barbara Müller, 1998
Transport an Nanopartikel gebundener Arzneistoffe durch natürliche und künstliche Membranen
- Peter Ramge, 1998
Untersuchungen zur Überwindung der Blut-Hirn-Schranke mit Hilfe von Nanopartikeln
- Hans-Peter Zobel, 1998
Entwicklung von Acrylat-Nanopartikeln als Arzneistoffträger für Antisense-Oligonukleotide