EP1610821A2 - Agent permettant de diagnostiquer et de traiter des tumeurs malignes de maniere photodynamique - Google Patents

Agent permettant de diagnostiquer et de traiter des tumeurs malignes de maniere photodynamique

Info

Publication number
EP1610821A2
EP1610821A2 EP04726487A EP04726487A EP1610821A2 EP 1610821 A2 EP1610821 A2 EP 1610821A2 EP 04726487 A EP04726487 A EP 04726487A EP 04726487 A EP04726487 A EP 04726487A EP 1610821 A2 EP1610821 A2 EP 1610821A2
Authority
EP
European Patent Office
Prior art keywords
chlorin
polyvinylpyrrolidone
therapy
agent
chlorine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04726487A
Other languages
German (de)
English (en)
Inventor
Peter Petrov
Tatsiana Trukhacheva
Henadz Isakau
Mikhail Haurylau
Mikhail Kaplan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haemato-Science GmbH
Original Assignee
Haemato-Science GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haemato-Science GmbH filed Critical Haemato-Science GmbH
Publication of EP1610821A2 publication Critical patent/EP1610821A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to an agent for the photodynamic diagnosis and therapy of oncological diseases based on chlorine E 6 compounds, as well as new medical uses of chlorine E 6 compounds.
  • Russian Patent No. 2152790 discloses an agent for the photodynamic diagnosis and therapy of oncological diseases which consists of 40 to 90% by weight of Chlorin E 6 and 60 to 10% by weight of polyvinylpyrrolidone.
  • Photosensitizers are required for photodynamic cancer therapy. These sensitizers are injected and accumulate predominantly in the cancerous cells. The production of cytostatic substances in the cancer cells that contain the photosensitizer is induced by targeted laser exposure at a certain wavelength. This leads to tumor necrosis.
  • sensitizers for this purpose are hematoporphyrins, phthalolocyanins and naphthalocyanins.
  • the sensitizers based on porphyrin have proven themselves due to their low phototoxicity and suitable sensitivity for the lasers to be used.
  • Chlorin E 6 has intense adsorption bands in the 660 ⁇ 10 spectral range nm, which is of particular importance for photodynamic therapy. However, the extinction coefficient for the hematoporphyrins is relatively low. For a successful photodynamic therapy, a higher concentration of this sensitizer must therefore be brought into the cancer cell. Since some of the porphyrins have phototoxicity, the advantage of chlorin E 6 is that they are rapidly excreted after administration. 24 hours after administration, only 4 to 6% of the amount administered can be detected in the human organism.
  • Chlorin E 6 and its salts are, however, relatively unstable, both in solution and in the lyophilized state at room temperature.
  • the invention is therefore based on the object of eliminating the above disadvantage and of providing an agent based on chlorine E 6 for photodynamic therapy which not only has a stability which is well suited for handling, even in solution, but also a substantially improved enrichment factor in the cancerous tissue compared to healthy tissue.
  • Another object of the invention is to provide further medical uses of Chlorin E 6 .
  • an agent for photodynamic therapy based on chlorin E 6 and its derivatives and polyvinylpyrrolidone which is characterized in that it contains chlorine E 6 and polyvinylpyrrolidone in a weight ratio of 1 :(> 1.5) or consists thereof ,
  • a weight ratio of chlorine E 6 to polyvinylpyrrolidone of 1: (> 1.5 to 25), preferably of 1: 2 is preferred preferably 1: 3, more preferably 1: 5, even more preferably 1:10, even more preferably 1:15, even more preferably 1:25.
  • the weight ratio is in the range of about 1: (5 to 25), preferably 1: (10 to 25), more preferably 1: (15 to 25), more preferably 1: (15 to 20).
  • Chlorin E 6 and polyvinylpyrrolidone are preferably present as a complex.
  • polyvinylpyrrolidone is expediently dissolved in an aqueous base suitable for injection and then, with constant stirring, chlorine E 6 in the amount of more than 1.5 and up to 25 parts by weight of PVP per 1 to achieve the desired composition Part by weight of chlorine E 6 is added and the mixture is stirred until a completely homogeneous mixture has formed.
  • the solution obtained can be sterile filtered and can be freeze-dried and stored in this form at normal temperature.
  • the formulation can also be prepared in such a way that it is suitable for the systemic and / or local action through parenteral, enteral and / or topical administration.
  • a preparation with 6 to 12 kDa is preferred as polyvinylpyrrolidone.
  • the derivatives of chlorin E 6 (13-carboxy-17- [2-carboxyethyl] -15-carboxymethyl-17, 18-transdihydro-3-vinyl-8-ethyl-2,7,12, 18-tetramethylporphine), such as
  • the corresponding 15-carboxyethoxymethyl or 15-formyl compounds, all of which naturally occur as accompanying substances of chlorin E 6 are suitable in the same way.
  • mixtures of chlorine E 6 with its derivatives can also be present in the complex according to the invention.
  • the agent according to the invention is normally administered in the form of an injectable solution.
  • incorporation into ointments or liniments for direct application to the skin is also possible.
  • a dosage of 0.5 to 10 mg / kg, preferably 1 to 7 mg / kg is recommended.
  • agent according to the invention in liquid or semi-solid pharmaceutical formulations.
  • chlorin E 6 is suitable for the production of medicaments for uses other than for tumor diseases.
  • chlorin E 6 shows good effectiveness on the skin, so that skin diseases can be treated well with chlorin E 6 and PVP-containing agents, both as preventive measures and for therapy.
  • Chlorin E 6 -PVP is particularly effective in fungal diseases, as well as in psoriasis and similar skin diseases. It is effective against dermatophytes, mold and yeast.
  • chlorin E 6 is surprisingly suitable for epilation, ie for hair removal.
  • the present invention thus furthermore relates to an agent for the prophylactic or therapeutic or cosmetic treatment of the skin, in particular for the treatment of fungal diseases of the skin, psoriasis or for hair removal, the agent comprising chlorin E 6 and PVP in any mixing ratio.
  • the weight ratios of the two components can include an excess of chlorine E 6 or an excess of PVP.
  • Weight ratios of chlorin E 6 to PVP of about 1: 0.1 to a considerable excess of polyvinylpyrrolidone compared to chlorin E 6 , in particular up to 1:25, are particularly suitable.
  • Weight ratios of 1: 1 are particularly preferred. But ratios of 1: (> 1, 5), 1: 5 or 1: 10 or 1: 1 5 are also suitable for the applications mentioned.
  • the following examples illustrate the effectiveness of the agent according to the invention in comparison with a known agent according to Russian chemical patent no. 21 52790 regarding tumor activity, and the effectiveness of chlorin E 6 for the treatment of the skin.
  • the accumulation dynamics of the photolon or the agent according to the invention were determined in the tumor tissues of the rats (lymphosarcoma pliss) and the healthy tissues (in the opposite skin of the thigh) with the aid of computer-controlled fluorescence spectrophotometry using the analyzer "LESA-6" (diagnostic laser “LGH 633 -25 “( Figure 1) observed.
  • Tables 1 to 4 show the individual and mean enrichment data for the preparation in the 1 2 rats.
  • Table 1 Accumulation dynamics of the Fotolon in the healthy tissues in rats with Pliss lymphosarcoma
  • Table 2 Accumulation dynamics of the Fotolon in the tumor tissue in the rats with lymphosarcoma Pliss.
  • Table 3 Dynamics of accumulation of the agent according to the invention in the healthy tissue of the rats with lymphosarcoma pliss
  • Table 4 Dynamics of accumulation of the agent according to the invention in the tumor tissue of the rats with lymphosarcoma pliss
  • the HET-CAM (Chorio-Allantois-Membrane) bioassay is important for the evaluation of effects on vessels and transplanted tumors in the context of photodynamic therapy.
  • the assay offers the advantage over animal models of qualitatively and quantitatively recording non-invasively in vivo morphological changes in the vessels and changes in blood perfusion / circulation.
  • the test approach In order to investigate the effect of phototoxic substances on the incubated chicken egg, there are numerous possibilities for the test approach with regard to the location of the application, the time of application and the criteria for the assessment and evaluation.
  • the CAM was selected as part of the extra embyronal vascular system as the application site.
  • the CAM is highly vascularized, transparent and develops very dynamically between days 3 and 12.
  • Chlorin E 6 was applied in a gel topically to the corresponding skin areas of a patient and left under occlusion for 30 minutes to act.
  • the irradiation was carried out with a laser at a wavelength of 662 nm for 3 to 5 minutes and in a dose of 36 to 60 J / cm 2 .
  • UVB radiation (without the addition of a medication) was carried out on skin areas damaged by psoriasis. The first result is a faster healing of the skin areas treated with PDT.
  • a small amount of the fungal tissue is taken from patients with fungal disease for pathological determination. A part of this is transferred to a nutrient medium. The resulting colonies are separated and separately subjected to photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • the individual fungal colonies are overlaid with a photosensitizer solution.
  • concentration of the photosensitizer in the solution varies (including 5, 10, 20% and without a photosensitizer solution as a control) to determine the concentration range in which the photosensitizer acts.
  • irradiation is carried out. Among other things, examines the frequency with which the radiation must be repeated and to what extent in order to achieve sufficient effectiveness.
  • Photodynamic therapy showed the greatest influence in the treatment of dermatophytes. The best results were obtained from the mushroom culture doors Trichophyton mentagrophytes and Trichophyton rubrum. In contrast, the PDT had no significant influence on the fungal culture Microsporum gypseum.
  • Chlorin E 6 Treatment of a patient with athlete's foot ( ⁇ spergillus fumigatus) by chlorin E 6 followed by radiation showed that the fungus regressed.
  • Treatment of a patient does not provide any reliable information on the actual effectiveness of Chlorin E 6 .
  • Treatments with Fotolon in different compositions (1: 1, 1:10) involve a larger number of patients.
  • the epilation of hair was carried out on different areas of hair on the patient.
  • the chlorin E 6 was incorporated into a commercially available gel at 0.1% and 0.2% and applied to the corresponding skin areas. After 30 minutes of exposure, the hairy surface was lasered for 3 to 5 minutes and an energy dose of 36 J / cm 2 or 60 J / cm 2 irradiated. The hair was then removed (razor, pincer). The thorax, groin, upper lip and lower abdomen were chosen as the hair surface. The radiation was repeated once a week within 2 to 4 weeks depending on the success of the treatment.
  • Chest most hair has not grown back, the hair that has grown back is very fine

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un agent à base de composés chlorine E6, qui permet de diagnostiquer et de traiter des maladies oncologiques de manière photodynamique. Cette invention se rapporte en outre à de nouvelles utilisations médicales desdits composés chlorine E6.
EP04726487A 2003-04-10 2004-04-08 Agent permettant de diagnostiquer et de traiter des tumeurs malignes de maniere photodynamique Withdrawn EP1610821A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10316566A DE10316566A1 (de) 2003-04-10 2003-04-10 Mittel für die photodynamische Diagnostik und Therapie von bösartigen Tumoren
PCT/EP2004/003809 WO2004089409A2 (fr) 2003-04-10 2004-04-08 Agent permettant de diagnostiquer et de traiter des tumeurs malignes de maniere photodynamique

Publications (1)

Publication Number Publication Date
EP1610821A2 true EP1610821A2 (fr) 2006-01-04

Family

ID=33038992

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04726487A Withdrawn EP1610821A2 (fr) 2003-04-10 2004-04-08 Agent permettant de diagnostiquer et de traiter des tumeurs malignes de maniere photodynamique

Country Status (3)

Country Link
EP (1) EP1610821A2 (fr)
DE (1) DE10316566A1 (fr)
WO (1) WO2004089409A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008534670A (ja) * 2005-04-07 2008-08-28 フォト・ダイアグノスティック・デバイシィズ・（ピーディーディー）・リミテッド 光増感剤とｍｒｉ増感剤
US8999933B2 (en) * 2006-01-18 2015-04-07 Biolitec Pharma Marketing Ltd Photodynamic cosmetic procedure and healing method

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5885557A (en) * 1996-02-08 1999-03-23 Estee Lauder Inc. Compositions useful in the phototherapeutic treatment of proliferative skin disorders
GB9700396D0 (en) * 1997-01-10 1997-02-26 Photocure As Photochemotherapeutic compositions
RU2152790C1 (ru) * 1999-05-12 2000-07-20 Мещерякова Аделия Леонидовна Средство для фотодинамической диагностики и терапии онкологических заболеваний
AU2003230808A1 (en) * 2002-04-05 2003-10-27 Candela Corporation High fluence rate activation of photosensitizers for dermatological applications

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004089409A2 *

Also Published As

Publication number Publication date
WO2004089409A2 (fr) 2004-10-21
WO2004089409A3 (fr) 2005-01-13
DE10316566A1 (de) 2004-10-28

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