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WO2002069929A1 - Systemes trifonctionnels pour maladies chroniques - Google Patents

Systemes trifonctionnels pour maladies chroniques Download PDF

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Publication number
WO2002069929A1
WO2002069929A1 PCT/DE2001/000848 DE0100848W WO02069929A1 WO 2002069929 A1 WO2002069929 A1 WO 2002069929A1 DE 0100848 W DE0100848 W DE 0100848W WO 02069929 A1 WO02069929 A1 WO 02069929A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifunctional
systems according
therapy
systems
body surface
Prior art date
Application number
PCT/DE2001/000848
Other languages
German (de)
English (en)
Inventor
Udo Dunzendorfer
Eva Dunzendorfer
Original Assignee
Udo Dunzendorfer
Eva Dunzendorfer
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 Udo Dunzendorfer, Eva Dunzendorfer filed Critical Udo Dunzendorfer
Priority to PCT/DE2001/000848 priority Critical patent/WO2002069929A1/fr
Publication of WO2002069929A1 publication Critical patent/WO2002069929A1/fr

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Classifications

    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to the provision of trifunctional systems with protein bodies, chemical active substances and biocompatible matrix substances for general diagnosis or for local, regional or general therapy of chronic diseases, particularly cancerous diseases or body defects in a uniform combination.
  • the invention is based on the objective of creating trifunctional systems for diagnosis and therapy which, through direct or indirect use, can detect and / or effectively influence complex processes in chronic diseases. Attempts are made to release metabolic substances that cause disease, which are detectable in high concentrations in the tissue, but not in the blood or urine, into the blood and to measure them there.
  • the trifunctional system is used therapeutically to bring active substances directly (locally) or regionally to the diseased location in high concentration instead of the usual systemic application, so that e.g. can have a better effect in cancer tissue.
  • This changed use of drugs or biocompatible matrix substances e.g. as a medicinal product is only possible in the trifunctional system, only because of this a significantly higher tissue concentration at the site of action is achieved.
  • the residence time of the substances in the tissue is prolonged by the use in the trifunctional system, so that as a result the medicinal products heal or the medication is delayed in the body.
  • this object is achieved by a uniform, trifunctional system consisting of protein bodies, variously usable substances and biocompatible matrix substances.
  • the trifunctional system can be used in the form of implants, injection solutions, tablets, dragées, skin creams or lotions.
  • a variety of methods are used for the treatment of cancer, which are modified depending on the cell type, degree of spread and recurrent cancer growth after primary therapy, which is described by the term multimodal therapy.
  • Therapeutically important is the ability of cancer cells to develop biochemical mechanisms under cytostatic treatment, which recognize drugs that are harmful to cancer cells and excrete them without effect via special processes (so-called multiple drug resistance, MDR mechanisms).
  • the present trifunctional system is a new combination of 1-2000 mg / m 2 body surface protein bodies, primarily immunoglobulms with one or more disease-specific cytostatics and possibly matrix substances. In the clinical application of these combinations under the local or regional
  • Organ areas such as the blood-forming bone marrow, the nervous system, liver function or the
  • Medicament combination consisting of 40 mg / m 2 body surface polyvalent, human immunoglobulin with the following variable proportions on 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and 20 mg / m 2 body surface palitaxcel.
  • a biocompatible matrix substance is added to this compound.
  • the medicament combinations according to the invention can contain, in addition to the commonly used constituents, in addition to the disease-specific active ingredients, solubilizers which lead to a further, recognizable increase in tissue penetration, such as, for. B. 0.4-0.8 mg m 2 body surface area nitroglycerin per solution for injection.
  • the active substances are released from the tissue by appropriate enzyme activities of amidases and / or esterases.
  • the polyvalent immunoglobulin can then bind to the ubiquitously formed receptors for F (ab) 2 and Fc components of the IgG, IgM, IgA protein bodies, the prerequisite for further therapeutic effects being given.
  • the matrix substance of lactic acid, glycolic acid, copolymer is gradually broken down. A large number of drug combinations in the trifunctional active system is shown in the pictures.
  • implantable plastics are used which are coated with the above-mentioned polyvalent protein bodies (e.g. immunoglobulins, human growth factors, or similar biofactors) and, in addition, can optionally contain various antibiotics.
  • polyvalent protein bodies e.g. immunoglobulins, human growth factors, or similar biofactors
  • these medicinal products can fill up smaller tissue defects by direct injection and wax in on site via a local foreign body reaction.
  • non-resorbable, coated, implantable biomaterials can be used to obliterate fistulas. Also with other defects such as In the case of incontinent bladder or other partially defective, biological closure systems, this implantable biomaterial can be used to fill the defect or to fill in the insufficient closure apparatus.
  • the advantageous embodiment can be obtained with a large number of plastics in the trifunctional active system, as can be seen in Figure 49. If you first use the active substances from the trifunctional combination in biological systems, protein bonds are broken down and the individual factors can be recorded with the corresponding, matrix-bearing, polyvalent antibodies. These complex test systems allow measurements of previously non-measurable, tissue-bound substances, since these substances are released into the bloodstream or into biological fluids from the tissue. In a second step of the test system, the blood can then be used to identify these substances with the assigned antibodies, either alone or bound to plastic carriers. This complex procedure of the test system is important for all diagnostic procedures that were previously only possible through tissue biopsy.
  • tissue factors in amyloid meres disease which is usually only shown directly by tissue examinations, can be extracted from the tissue binding and measured in the blood after suitable pretreatment, as can be seen from the example of the factor ß-microglobulin (Table 7).
  • Drug combination consisting of 40 mg / m2 body surface of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA
  • Protein body here natural immunoglobulins (IgA, IgG, IgM)
  • Illustration 1 Table 1 describes the effect of this combination of drugs in 10 patients with localized prostate cancer.
  • the weekly treatment of prostate cancer with direct injection of the new drug into the prostate for 12 weeks has significantly reduced the volume of the prostate and prostate cancer in all patients.
  • the general condition and. the special urological complaints improved significantly.
  • the tumor marker normalized in the blood, while no side effects for the hematopoietic bone marrow, liver and kidney function were detectable.
  • Table I Changes in parameters during therapy with protein bodies and palicatel measured by: Volume: prostate volume, tumor marker PSA: prostate-specific antigen, clinic: Kamosfky index, scaling: 0.2-1.0 uroflow (urine flow measurement), toxicity using: WBC: leukocytes, RBC : Erythrocytes. PLT: platelets, disease stage: tumor stage
  • Table 2 describes the effect of this combination of medications in 8 patients with recurrent bladder cancer after pretreatment.
  • the weekly treatment of bladder cancer with direct injection of the new drug into the bladder over 12 weeks has significantly reduced the volume of bladder cancer in all patients or completely destroyed the cancerous tissue.
  • the general condition and the special urological complaints such as Blood urine improved significantly.
  • Table 2 Changes in the parameters when protein bodies and Palicatel were used in combination with cytology, hematuria, TPA as a tumor marker for bladder carcinoma, karnosf y index, (scaling: 0.2-1.0) uroflow (urine flow measurement), side effects on the bone marrow (toxicity)
  • WBC Leukocytes
  • RBC Erytlirocytes.
  • PLT platelets
  • stage tumor stage PT1-4 Nx Mx
  • Table 3 describes the effect of this combination of medications in 5 patients with exulcer-end breast cancer.
  • the weekly treatment of breast cancer with direct injection of the new drug into the tumor region over a period of 12 weeks significantly reduced the volume of the cancer region in all patients, and the wound healed spontaneously. The general condition and the special complaints in the wound area improved significantly.
  • the tumor marker normalized in the blood, while no side effects for the hematopoietic bone marrow, liver and kidney function were detectable.
  • Table 3 Changes in the parameters using protein bodies and palitaxcel combined using Tumorulcus CA 15-3 as a tumor marker for breast cancer, Karnosfky Index (scaling: 0.2-1.0), flat effects on the bone marrow (toxicity)
  • WBC leukocytes
  • RBC erythrocytes.
  • PLT platelets
  • stage tumor stage PT1-4 Nx Mx
  • the medicament combinations according to the invention can also contain solubilizers in addition to the active ingredients, which lead to a further increase in tissue penetration, for example. 0.4-0.8 mg / m2 body surface area nitroglycerin per solution for injection. Similar results are possible and effective with the combination of polyvalent immunoglobulin, 20 mg / m2 palitaxcel, the matrix substance made from lactic acid, glycolic acid, copolymer and other additives such as diethylstilbestrol:
  • Table 4 describes the effect of the combination of protein bodies, palitaxcel and polyestradiol in 10 patients with locally advanced prostate cancer. Weekly treatment of prostate cancer with direct injection of the combination into the prostate for 12 weeks has significantly reduced prostate and prostate cancer volume and restored operability in all patients. The general condition and the special urological complaints improved significantly. As a further sign of effectiveness, the tumor marker normalized in the blood, while no side effects on the hematopoietic bone marrow, the liver and kidney function were detectable.
  • Table 4 Changes in the parameters during therapy with protein bodies and palataxcel measured by: volume: prostate volume, tumor marker PSA: prostate specific antigen, clinic: Karnosfky index, scaling: 0.2-1.0 uroflow (urine flow measurement), toxicity using: WBC: leukocytes, RBC : Erythrocytes.
  • PLT platelets, disease stage: tumor stage
  • Matrix substances e.g. Non-absorbable, coated, implantable biomaterials can be used for the obliteration of fistulas and / or other defects such as, for example, in the case of incontinent bladder or other partially defective, biological closure systems for feeding the closure apparatus.
  • incontinent bladder or other partially defective, biological closure systems for feeding the closure apparatus.
  • up to 2 ml of coated material were fed longitudinally to the female urethra at 90, 180, 270 degrees to treat the incontinent bladder.
  • An improved indirect sphincter function could be achieved with the injection.
  • LAC liposomal anthracyclines
  • LAC liposomal anthracyclines
  • CISPLATIN 5. 1.0 - 600 mg / m2 body surface from polyvalent, human immunoglobulin with the following
  • DOXORUBICIN 8. 1.0 - 600 mg / m2 body surface from polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and etoposide or its analogues in a concentration of 40 -300 mg / m2 body surface
  • HYDROXYUREA 12. 1.0 - 600 mg / m2 body surface from polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and irinotectan or its analogues in a concentration of 50 mg m2-1.0g / m2 body surface
  • MELPHALAN 15.1.0 - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA ' and methotrexate or its analogues in a concentration of 10- 100mg / m2 body surface
  • MITOXANE 18.1.0 - 600 mg / m2 body surface of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and Thiotepa or its analogues in a concentration of mg / m2 Body surface
  • TOPOTECTAN 21.1.0 - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and methyl guazone or its analogs in a concentration of 10 mg m2- 1.5 g / m2 body surface
  • 25.1.0 - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and hexamethylenediacetamide or its analogues in a concentration of 30 mg / m2 -450mg / m2 body surface
  • 35.1.0 - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and spirohydantoin mustard or its analogs in a concentration of 20- 450mg / m2 body surface
  • Spirohydantoin mustard 36.1 ⁇ 0 - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8 g IgA and rapamycin or its analogues in a concentration of 1.0 mg / m2 -180mg / m2 body surface
  • Menogaril 39.1 $ - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following parts per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, .0.2-1.8 g IgA and HEPSULFAM or its analogues in a concentration of 10 mg / m2 - 1.0 g / m2 body surface
  • Carbamide acid 48.1.0 - 600 mg / m2 body surface made of polyvalent, human immunoglobulin with the following proportions per 100 ml: 2.0-6.0 g IgG, 0.2-2.0 g IgM, 0.2-1.8.g IgA and thalidomide or its analogs in a concentration of 100 mg / m2- 1.5 g / m2 body surface
  • Matrix substances are usually resorbable, metabolically harmless protein bodies or non-resorbable, biocompatible plastics. The binding with the other components from the trifunctional system takes place via ligand activation of the matrix.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des systèmes trifonctionnels qui sont utilisés dans le cadre du diagnostic et du traitement de maladies chroniques. Ces systèmes trifonctionnels représentent des unités à fonction biologique choisies parmi les composants suivants : des protéines, des substances actives chimiques et des substances matricielles biocompatibles. Les domaines d'application biologique de ces systèmes trifonctionnels comprennent 1. le diagnostic de maladies à processus chroniques, par libération de facteurs d'essai préalablement liés aux tissus dans des solutions biologiques, au lieu d'une biopsie des tissus, 2. la thérapie locale et régionale avec des substances actives au lieu d'une thérapie systémique et 3. le remplissage de tissu défectueux avec des matériaux dont la surface présente un revêtement bioactif, respectivement en fonction d'utilisations ciblées des systèmes trifonctionnels.
PCT/DE2001/000848 2001-03-06 2001-03-06 Systemes trifonctionnels pour maladies chroniques WO2002069929A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/DE2001/000848 WO2002069929A1 (fr) 2001-03-06 2001-03-06 Systemes trifonctionnels pour maladies chroniques

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015640A1 (fr) * 1993-01-12 1994-07-21 Anthony George Gristina Procedes et compositions pour application directe a forte concentration d'anticorps, produisant une immunite passive
DE19732323A1 (de) * 1996-08-06 1998-06-04 Dunzendorfer Udo Priv Doz Dr M Medikamentenkombination zur erhöhten Wirkstoffkonzentration in Geweben
US6033719A (en) * 1996-04-25 2000-03-07 Medtronic, Inc. Method for covalent attachment of biomolecules to surfaces of medical devices
WO2000040269A2 (fr) * 1999-01-05 2000-07-13 Lee Clarence C Compositions pharmaceutiques destinees au traitement des tissus malades
US6123939A (en) * 1989-08-04 2000-09-26 Berlex Laboratories, Inc. Anti-neoplastic drugs in cancer therapy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6123939A (en) * 1989-08-04 2000-09-26 Berlex Laboratories, Inc. Anti-neoplastic drugs in cancer therapy
WO1994015640A1 (fr) * 1993-01-12 1994-07-21 Anthony George Gristina Procedes et compositions pour application directe a forte concentration d'anticorps, produisant une immunite passive
US6033719A (en) * 1996-04-25 2000-03-07 Medtronic, Inc. Method for covalent attachment of biomolecules to surfaces of medical devices
DE19732323A1 (de) * 1996-08-06 1998-06-04 Dunzendorfer Udo Priv Doz Dr M Medikamentenkombination zur erhöhten Wirkstoffkonzentration in Geweben
WO2000040269A2 (fr) * 1999-01-05 2000-07-13 Lee Clarence C Compositions pharmaceutiques destinees au traitement des tissus malades

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