Biolitec Pharma Marketing Ltd

Ceramoptec Industries, Inc.

Biolitec Unternehmensbeteiligungs II Ag

Saint Gobain Isover

Biolitec Unternehmensbeteilligungs Ll Ag

Volker Albrecht

Arno Wiehe

Susanna Gräfe

Wolfgang Neuberger

Burkhard Gitter

Dietrich Scheglmann

Daniel Aicher

Christian B W Stark

Nikolay Nifantiev

Alfred Fahr

Susanna Graefe

Rainer Haag

Stefan Spaniol

Hagen Von Briesen

Gerhard Wieland

Danilo Castro

Matthias Epple

Benjamin Florian Hohlfeld

Anton Zysik

Harald Ligtenberg

Klaus Langer

Hartwig Richard Arthur Golf

Hans-Ulrich Reißig

Jens Meyer

Hans-Peter Bode

Beate Roeder

Kathirvel Ganesan

Claus Bissinger

Claudia S Gutsche

Michael Staegemann

Sylvia Wagner

Karin Löw

Annegret Preuss

Beate Röder

Matthias Wacker

Janine Schwiertz

Nikolay E Nifantiev

Karl-Heinz Voepel

Gerhard D Wieland

Karin Low

Thomas Knobloch

Annegret Pruess

Susanna Grafe

Beate Roder

Gerard Farmer

The present invention provides biologically active compounds and methods to obtain biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of non-tumorous indications such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders. As the compounds exhibit also toxicity against targets (tumor cells, bacteria, inflammation-related cells) without light these biologically active compounds may also be used for the light-independent treatment of such indications. Preferred embodiments of the present invention consist of methods to synthesize metal or half-metal complex structures incorporating one or more substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyldipyrrin) units. These dipyrromethenes (dipyrrins) can carry a variety of different substituents in the 4-position enabling a fine tuning of their biological or amphiphilic/hydrophilic properties. Another object of the present invention is to provide amphiphilic compounds with a higher membrane affinity and increased efficacy.

Application of metal complexes in anti-tumor and anti-bacterial therapy

Biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders are provided as well as providing methods to obtain them in pharmaceutical quality. In addition, conjugates are provided in which these photosensitizers are attached to water-soluble polymers via cleavable linkers that can be cleaved in the body under specific conditions. Another embodiment consists of formulating the desired tetrapyrrole photosensitizer into a pharmaceutical formulation to be injected into the body avoiding undesirable effects like solubility problems or delayed pharmacokinetics of the tetrapyrrole systems.

Conjugates of porphyrinoid photosensitizers and glycerol-based polymers for photodynamic therapy

Biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, opthamological or urological disorders are provided as well as providing methods to obtain them in pharmaceutical quality. One embodiment consists of a method to synthesize a porphyrin with a defined arrangement of meso-substituents and then converting this porphyrin system to a chlorin system by dihydroxylation or reduction, and if more than one isomer is formed separate them by chromatography either on normal or reversed phase silica. In another embodiment the substituents on the porphyrin are selected to direct the reduction or dihydroxylation to the chlorin so that a certain isomer is selectively formed. Another embodiment is to provide amphiphilic compounds with a higher membrane affinity and increased PDT-efficacy. In other embodiments the nucleophilic substitution on pentafluorophenyl-substituted tetrapyrroles is used to obtain compounds with a high PDT-efficacy. In another embodiment substituents are identified that via their steric and/or electronic influence direct the dihydroxylation or reduction with diimine so that one isomer is favored. Another embodiment consists of formulating the desired tetrapyrrole photosensitizer into a pharmaceutical formulation to be injected into the body avoiding undesirable effects like solubility problems or delayed pharmacokinetics of the tetrapyrrole systems.

Specifically meso-substituted porphyrins and chlorins for photodynamic therapy

Methods and devices to eliminate, reduce, destroy and/or inhibit undesired body fluid species, such as pathogen microbes and deteriorated or malignant cells in complex environments like blood, serum and other body fluids are provided. In preferred embodiments, an antimicrobial photodynamic therapy (PDT) treatment is given that effectively inactivates, reduces and/or destroys both Gram (&#x2212;) and Gram (+) bacteria in complex body fluids. Methods to enhance antimicrobial PDT activity include administering a photosensitizer to bacteria-contaminated fluid, after a dwell time guiding bacteria-contaminated fluid with photosensitizer through a channel, emitting radiation preferably in an intermittent manner, and restoring treated body fluids to corresponding body regions. Electromagnetic radiation is preferably delivered intermittently with pulse width based on treatment parameters. Additionally, the method/device diminishes adverse host's inflammatory responses by neutralizing the biological activity of pathogenic microorganism fragments and reducing and/or removing pathogenic microorganism fragments responsible for it.

Enhanced anti-microbial PDT

Biologically active compounds are provided that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders as well as providing methods to obtain them in pharmaceutical quality. One embodiment consists of a method to synthesize a porphyrin with a defined arrangement of meso-substituents and then converting this porphyrin system to a chlorin system by dihydroxylation or reduction, and if more than one isomer is formed separate them by chromatography either on normal or reversed phase silica. In another embodiment the substituents on the porphyrin are selected to direct the reduction or dihydroxylation to the chlorin so that a certain isomer is selectively formed. Another embodiment is to provide amphiphilic compounds with a higher membrane affinity and increased PDT-efficacy. In another embodiment a method to reductively cleave the osmate(VI)ester avoiding the use of gaseous HS is provided. In another embodiment substituents are identified that via their steric and/or electronic influence direct the dihydroxylation or reduction with diimine so that one isomer is favored. Another embodiment consists of formulate the desired isomer into a liposomal formulation to be injected avoiding undesirable effects like solubility problems or delayed pharmacokinetics of the tetrapyrrole systems.

[object Object]

Antimicrobial molecular conjugates for the treatment and prevention of infectious diseases caused by pathogenic microorganisms in human and animals are provided. The conjugates are of the class of compounds of dihydroxychlorins or &#x3b2;-functionalized chlorins connected to carbohydrate moieties and having the general formula 

Glyco-substituted dihydroxy-chlorins and &#x3b2;-functionalized chlorins for anti-microbial photodynamic therapy

Compositions, which are stable in storage, and a method of production of pharmaceutical based nanoparticulate formulations for photodynamic therapy comprising a hydrophobic photosensitizer, human serum albumin (HSA) and stabilizing agent are provided. These nanoparticulate formulations provide therapeutically effective amounts of photosensitizer (PS) for parenteral administration. In particular, tetrapyrrole derivatives can be used as photosensitizers whose efficacy and safety are enhanced by such nanoparticulate formulations. A method of preparing the HSA-based nanoparticles under sterile conditions is also provided. In one of the preferred embodiments of the present invention temoporfin, a hydrophobic PS, is formulated as a nanoparticle for parenteral administration. The formulations are useful for treating hyperplasic and neoplasic conditions, inflammatory problems, and more specifically to target tumor cells.

Nanoparticle carrier systems based on human serum albumin for photodynamic therapy

The present invention provides biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PdT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, ophthalmological or urological disorders. The compounds are of the class of &#x3b2;-functionalized hydroxy- and dihydroxy-chlorins having the general formula 

Application of &#x3b2;-functionalized dihydroxy-chlorins for PDT

A special photosensitizer formulation and Photodynamic Therapy method for treating choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) is provided. CNV is a major cause for vision loss in elderly patients. A special drug delivery formulation is used to encapsulate the hydrophobic photosensitizer, preferably a pegylated liposome. This improves the solubility and therapeutic index of the photosensitizers. In one preferred embodiment, a pegylated photoactive agent remains confined in the intravascular compartment of neovasculature for a longer duration. Thus efficient elimination of neovascular proliferation and minimal damage to extravascular tissue and normal vessels is ensured. In this method, a hydrophobic photosensitizer, that is able to photochemically destroy neovessels, is injected into the patient. CNV irradiation with a non-thermal laser follows after a predefined time interval. The excited photosensitizer photocoagulates newly formed blood vessels thereby improving the vision and preventing further loss of vision.

Pegylated compounds for age-related macular degeneration

Innovative non-surgical methods and compositions are provided for administering PDT to promote tissue regeneration or augmentation while minimizing scarring and risk of infection. Among several areas of application, is the treatment of acute and chronic wounds which have afflicted epidermal and connective tissue layers of the body. Another application area is as cosmetic surgery/treatments, including: reducing wrinkles, sulcus, scars (acne or traumatic caused), sequelae cellulite, as well as for other skin irregularities, to give a smoother skin surface. This invention consists of a collagen based or other suitable biodegradable supporting matrix which is embedded with a liposomal loaded photosensitizer. In one embodiment of this invention a liposomal formulated photosensitizer is first injected at the site followed by collagen implantation and PDT treatment. In another embodiment a liposomal formulated photosensitizer is incorporated in the collagen. Generally 30 minutes after collagen is mixed with photosensitizer the light activation is done. The matrix may also carry important growth factors and cytokines, which promote fibroblast cell migration and proliferation, to the wound site. Microbial infection at the wound site can also be controlled by antibacterial PDT.

Photodynamic cosmetic procedure and healing method

Pharmaceutical pegylated liposomal formulations for photodynamic therapy are presented. The pegylated liposomal formulation provides therapeutically effective amounts of the photosensitizer for intravenous administration. At least one of the phospholipids in the liposomes has been linked with poly ethylene glycol (PEG) as an integral part of the phospholipids. The formed pegylated liposomes contain the hydrophobic photosensitizer within the lipid bilayer membrane. Pegylation of liposomes carrying the hydrophobic photosensitizer helps to maintain the drug level within the therapeutic window for longer time periods and provides the drug a longer circulating half life in vivo. Further the pegylated formulation of hydrophobic photosensitizers shows improved pharmacokinetics over standard non-liposomal formulations thus enhancing the efficacy of PDT with the pegylated liposomal formulations.

Pegylated liposomal formulations of hydrophobic photosensitizers for photodynamic therapy

The present invention provides pharmaceutical photosensitizer-loaded nanoparticle formulations and their methods of preparation for photodynamic therapy, comprising a hydrophobic or hydrophilic photosensitizer, nanoparticulate calcium phosphate and in certain cases auxiliary reagents such as stabilizers. The calcium phosphate-based nanoparticle formulations of the present invention provide excellent storage stability and therapeutically effective amounts of photosensitizer for intravenous or topical administration. In a preferred embodiment, tetrapyrrole derivatives such as porphyrins, chlorins and bacteriochlorins, are the preferred hydrophobic photosensitizers to be formulated in calcium phosphate nanoparticle formulations for photodynamic tumor therapy. Additionally, 5,10,15,20-tetrakis(4-phosphonooxyphenyl)porphine (pTPPP) is a preferred hydrophilic photosensitizer for photodynamic tumor therapy. In another preferred embodiment, hydrophilic cationic and anionic photosensitizers, especially those of the phenazinium, phenothiazinium and xanthenes series have been found to inactive pathogen bacteria and are the preferred photosensitizers to be formulated in calcium phosphate nanoparticle formulations for antibacterial photodynamic therapy. In another embodiment, photosensitizing nanoparticle formulations are useful to locate cells, tissues or bacteria by using fluorescence imaging methods.

Calciumphosphate-based nanoparticles as carrier-systems for photodynamic therapy

The present invention relates to improved methods of formulations of hydrophobic photosensitizers, and their precursors, for mucosal administration. The formulation of the invention comprises of hydrophobic photosensitizers which have been incorporated into suitably sized liposomes. Additionally, these formulations include the incorporation of PS-loaded liposomes into a copolymer matrix. The liposome of the present invention allows the hydrophobic photosensitizers to be incorporated into the thermogel matrix and thus promoting intimate contact between the formulation and the mucosal layer for enhanced drug absorption.

Gel-formulations of hydrophobic photosensitizers for mucosal applications

The present invention provides methods and compositions for increasing the effectiveness of photodynamic therapy ('PDT') and for reducing the duration of skin phototoxicity associated with PDT treatment. The disclosed methods generally include the administration of a lipid composition before, during, or after the administration of photosensitizers used in the PDT treatment protocol. The lipids are preferably phospholipids. It was discovered that the disclosed methods resulted in a more rapid clearance of photosensitizers from the skin and other tissue of patients, which results in a shorter period of skin phototoxicity after PDT treatment. The present invention also provides a composition which is preferably comprised of non-polar photosensitizers and phospholipids.

Methods and compositions for improving photodynamic therapy through administration of lipids

A new treatment regime is presenter using a low concentration formulation at a low dosage of hydrophobic photosensitizers (PS) that shows improved pharmacokinetics and an effective method for photodynamic therapy ('PDT'). The new formulation has better pharmacological effect compared to standard photosensitizer formulation with standard dosage. It was found that PDT treatments using the disclosed low concentration formulations provide for more accurate, more efficient and more convenient dosing. It was found that the inventive formulation; (1) reduces the time for a therapeutically effective level of photosensitizer to accumulate in diseased tissue; and, (2) reduces the time for achieving a sufficient ratio of photosensitizer in diseased tissue vs. healthy tissue. As a result, the formulation of the invention reduces the time interval between PS application/administration and irradiation (the drug-light interval or 'DLI') and can provide for a &#x201c;same day&#x201d; PDT treatment option. The inventive formulation can be used for PDT treatment regimes where photosensitizers are administered in at least one preselected dose, including a low concentration therapy for PDT. In particular, when meta-(Tetrahydroxyphenyl)Chlorin (m-THPC) is the photosensitizer, then a concentration of 0.8 mg/ml to 0.04 mg/ml in a mixture of pure propylene glycol and ethanol in a 3:2 volume ratio accumulates in diseased tissue and differentiates between diseased tissue and normal tissue sufficiently quickly for 'one day' or overnight administration and activation treatment procedures to be possible.

Photosensitizer formulations and their use

Growing community of inventors

Jena, Germany

Volker Albrecht