EP1100475A1 - Verwendung von arzneistoffbeladenen nanopartikel zur behandlung von krebs - Google Patents

Verwendung von arzneistoffbeladenen nanopartikel zur behandlung von krebs

Info

Publication number
EP1100475A1
EP1100475A1 EP99926509A EP99926509A EP1100475A1 EP 1100475 A1 EP1100475 A1 EP 1100475A1 EP 99926509 A EP99926509 A EP 99926509A EP 99926509 A EP99926509 A EP 99926509A EP 1100475 A1 EP1100475 A1 EP 1100475A1
Authority
EP
European Patent Office
Prior art keywords
nanoparticles
treatment
mammal
cancer
substance
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.)
Ceased
Application number
EP99926509A
Other languages
English (en)
French (fr)
Inventor
Bernhard A. Sabel
Jörg KREUTER
Svetlana Gelperina
Ulrike SCHRÖDER
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.)
NanoPharm AG
Original Assignee
Medinova Medical Consulting 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 Medinova Medical Consulting GmbH filed Critical Medinova Medical Consulting GmbH
Publication of EP1100475A1 publication Critical patent/EP1100475A1/de
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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 present invention relates to the use of drug-loaded nanoparticles for preparing a medicament for the treatment of cancer, particularly for the treatment of cancer in the brain, even more particularly for the treatment of brain cancer in humans.
  • the invention also relates to a process for the treatment of brain cancer, particularly for the treatment of brain cancer in humans, by ad ⁇ iinistering an effective amount of nanoparticles containing a substance which has effect in the cancer treatment or has immunosuppressive effects.
  • blood brain barrier refers to the bbb in the narrower sense, i. e. in the sense this term is used usually by a person skilled in the medical field, as well as to the blood spinal barrier and blood retina barrier.
  • nanoparticles prepared in accordance with teachings of the prior art, particularly of the above two Patent Applications may be loaded with a substance having effect in the treatment of cancers, particularly having effect in the treatment of cancers in the brain, for example in humans, in an effective amount and may then be coated with a suitable surfactant so as to allow that drug-loaded nanoparticles to pass across the bbb and to deliver the effective drug to the site where it may exhibit its anticancer and/or immunosuppressive activity. It was particularly found that, by a suitable selection of the combination drug/surfactant, an effective use of such nanoparticles loaded with the drug and coated with a surfactant in the treatment of cancers, particularly of cancers in the brain, may be pro viced.
  • the invention relates to the use of nanoparticles made of a polymeric material, said nanoparticles comprising said polymeric material, one or more substance(s) physiologically effective in the treatment of cancer upon delivery to a mammal, one or more stabilizer(s) for said nanoparticles allowing targeting of said physiologically effective substance(s) to a specific site within or on said mammalian body and/or a surfactant coating on said nanoparticles, said nanoparticles optionally being provided within a physiologically acceptable carrier and/or diluent allowing the delivery of said nanoparticles to the target within said mammal after administration, for the manufacture of a medicament for the treatment of cancer in said mammal.
  • the treatment of cancer is a treatment of cancer in the brain.
  • the brain cancer treatment is a treatment to a human.
  • the terms "cancer” and “tumor(s)” are used in the description and claims in a synonymous manner.
  • the nanoparticles used in the present invention for the cancer treatment are nanoparticles which mainly consist of three major components, i. e. the polymeric material which is used to form a wall either incorporating the drug or physiologically effective substance(s) or containing said substance(s) adsorbed or absorbed thereto, e. g. onto its surface; the physiologically effective substance or substances contained within or on said nanoparticle; and a stabilizer or more than one stabilizer allowing the passage of said nanoparticle across the bbb.
  • the present invention comprises as one of the preferred embodiments the use of said nanoparticles, wherein said nanoparticles comprise particles of said polymeric material having a diameter of below 1,000 nm, preferably of from 1 to 1,000 nm.
  • the invention relates to the use of said nanoparticles, wherein said polymeric material the nanoparticles are consisting of is selected from the group consisting of polyacrylates, polymethacrylates, poly-cyanoacrylates, polyacrylamides, polylactates, polyglycolates, polyanhydrates, polyorthoesters, gelatin, polysaccharides, -dbumin, polystyrenes, poly vinyls, polyacro ⁇ ein, polyglutaraldehydes and derivatives, copolymers and rnixtures thereof.
  • polyacrylates polymethacrylates, poly-cyanoacrylates, polyacrylamides, polylactates, polyglycolates, polyanhydrates, polyorthoesters, gelatin, polysaccharides, -dbumin, polystyrenes, poly vinyls, polyacro ⁇ ein, polyglutaraldehydes and derivatives, copolymers and rnixtures thereof.
  • the nanoparticles according to the invention there is/are provided within or on said nanoparticles (incorporated, absorbed and/or adsorbed) one or more substances which are physiologically effective in the treatment of cancer upon delivery to a mammal.
  • the substances may be a single substance or may be two or even more substances which may act on the human body on a separate route or on a combined route or even synergistic route.
  • said physiologically effective substance(s) to be delivered to said mammal comprise(s) one or more chemotherapeutic agent(s) for the cancer treatment, particularly for the treatment of cancer in the brain of said mammal, more particularly for the treatment of cancer in the human body, i. e. the brain.
  • chemotherapeutic agent(s) for the cancer treatment particularly for the treatment of cancer in the brain of said mammal, more particularly for the treatment of cancer in the human body, i. e. the brain.
  • chemotherapeutic anticancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural anticancer products, hormones, metal coordination complexes and mixtures thereof.
  • chemotherapeutic anticancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural anticancer products, hormones, metal coordination complexes and mixtures thereof.
  • nitroso ureas e. g. Carmustine (BCNU), Lomustine (CCNU), Semustine (methyl- CCNU) and Nimustine (ACNU);
  • BCNU Carmustine
  • CCNU Lomustine
  • CCNU Semustine
  • ACNU Nimustine
  • folic acid analogs e. g. Methotrexate
  • - purine analogs e. g. Mercaptopurine and Azathioprine
  • - vinca alkaloids e. g. Vinblastine, Nincristine and Vindesine
  • epipodophyllotoxins e. g. Etoposide and Teniposide
  • antibiotics e. g. Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Bleomycin A2, Mitomycin C and Mitoxantrone;
  • - estrogens e. g. Diethyl stilbestrol
  • - gonadotropin-releasing hormon analogs e. g. Leuprolide, Buserelin and Goserelin
  • antiestrogens e. g. Tamoxifen and Ammoglutethimide
  • a critical component of the nanoparticles used in the present invention is/are the stabilizer(s).
  • only one stabilizer is used whereby a passage of the bbb by said nanoparticles loaded with the anticancer drugs can be afforded in a successful way, and the anticancer drugs in said nanoparticles are directed to the tumor site in the brain in a high concentration.
  • the other critical component of the nanoparticles used in the present invention are the surfactant materials of the coating which materials are belonging to the same group of compounds as the above.
  • the stabilizer may be present in the nanoparticles used in accordance with the present invention as a result of the manufacturing steps either in small remaining amounts or may form the coating allowing the passage of the effective substance(s) across the bbb.
  • the separate coating may be provided.
  • the outside wall of the nanoparticles used in the present invention is coated with the material allowing the passage of the bbb in a surprising manner.
  • the application of the coating or the provision of the stabilizer in such nanoparticles is basically described in the above-mentioned International Patent Applications the disclosures of which are incorporated herein by reference.
  • the material(s) of the stabilizer/ surfactant is/are selected selected from the group consisting of stabilizers/surfactants which allow a passage of said nanoparticles including said physiologically effective substance(s) across the blood brain barrier in said mammal and stabilizers/surfactants which allow a release of said physiologically effective substance(s) from said nanoparticles and a passage of said substance(s) across the blood brain barrier separate from said nanoparticles.
  • said stabilizer/surfactant comprises a substance selected from the group consisting of polysorbates, dextrans, carboxylic acid esters of multifunctional alcohols, polyoxamers, polyoxamines, alkoxylated ethers, alkoxylated esters, alkoxylated mono-, di- and triglycerides, alkoxylated phenols and diphenols, substances of the Genapol R and Bauki R series, metal salts of carboxylic acids, metal salts of alcohol sulfates, and metal salts of sulfosuccinates and mixtures of two or more of said substances.
  • said stabilizer/surfactant comprises a substance selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 81, polysorbate 85, dextran 12.000, dextran 70,000, fatty acid esters of glycerol and sorbitol as glycerol monostearate, sorbitan monostearate and sorbitan monooleate, polyoxamer 188 (Pluronic R F68), ethoxylated ethers, ethoxylated esters, ethoxylated triglycerides, ethoxylated phenols and diphenols, metal salts of fatty acids and of fatty alcohol sulfates, more preferably the sodium salts of fatty acids and of fatty alcohol sulfates
  • the most preferred stabilizers/surfactant materials are selected from the group consisting of polysorbate 80, polysorbate 85, dextran 12,000 or dextran 70,000 and mixtures thereof and mixtures of said stabilizers with other stabilizers. With the latter compounds, a superior use of the nanoparticles in the anticancer treatment can be achieved, particularly in the treatment of brain cancers in humans.
  • said carrier and/or diluent which is used for the aclministration of the nanoparticles used in the present invention is/are selected from the group consisting of water, physiologically acceptable aqueous solutions containing salts and/or buffers and any other solution acceptable for administration to a mammal.
  • nanoparticles comprising said polymeric material, one or more substance(s) physiologically effective in the treatment of cancer upon delivery to a mammal, one or more stabilizer(s) for said nanoparticles allowing targeting of said physiologically effective substance(s) to a specific site within said mammalian body and/or a surfactant coating on said nanoparticles, said nanoparticles optionally being provided within a physiologically acceptable carrier and/or diluent allowing the delivery of said nanoparticles to the target within said mammal after administration, for the treatment of cancer in said mammal.
  • a process for the treatment of cancer particularly of brain cancer, in mammals, said process comprising the step of administering to said mammals nanoparticles made of a polymeric material, said nanoparticles comprising said polymeric material, one or more substance(s) physiologically effective in the treatment of cancer upon delivery to a mammal, one or more stabilizer(s) for said nanoparticles allowing targeting of said physiologically effective substance(s) to a specific site within said mammalian body and/or a surfactant coating on said nanoparticles, said nanoparticles optionally being provided within a physiologically acceptable carrier and/or diluent allowing the delivery of said nanoparticles to the target within said mammal after administration, in an amount effective for the treatment of cancer.
  • the administration is an i.v. administration. It is particularly preferred that the treatment is a treatment of brain cancer, e. g. in mammals as for example humans.
  • the invention is further exemplified by the subsequent example which, however, should not be understood to limit the invention.
  • the anti-tumor effect of doxorubicin preparations was tested in rats with an intracranially transplanted glioblastoma 101/8. This tumor is known to have a substantial number of receptors to the epidermal growth factor.
  • mice were treated with 1.5 mg/kg x 3 of doxorubicin which makes a total course dose of 4.5 mg/kg (the total dose for mice is usually 7 to 8 mg/kg).
  • the drugs were administered i/v on the day 2 (48 h after implantation of the tumor), day 5 and day 8 after tumor implantation.
  • Drug preparations were administered as usual in saline or in 1 % Tween R 80 .
  • the suspension was added with 1 % Tween R 80 with stirring. The mixture was incubated for 2 h.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Nanotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP99926509A 1999-06-02 1999-06-02 Verwendung von arzneistoffbeladenen nanopartikel zur behandlung von krebs Ceased EP1100475A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1999/003838 WO2000074658A1 (en) 1999-06-02 1999-06-02 Use of drug-loaded nanoparticles for the treatment of cancers

Publications (1)

Publication Number Publication Date
EP1100475A1 true EP1100475A1 (de) 2001-05-23

Family

ID=8167319

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99926509A Ceased EP1100475A1 (de) 1999-06-02 1999-06-02 Verwendung von arzneistoffbeladenen nanopartikel zur behandlung von krebs

Country Status (4)

Country Link
EP (1) EP1100475A1 (de)
JP (1) JP2003501379A (de)
AU (1) AU4373499A (de)
WO (1) WO2000074658A1 (de)

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AU3176097A (en) 1997-06-13 1998-12-30 Medinova Medical Consulting Gmbh Drug targeting system, method of its preparation and its use
US7153525B1 (en) 2000-03-22 2006-12-26 The University Of Kentucky Research Foundation Microemulsions as precursors to solid nanoparticles
AUPR011700A0 (en) 2000-09-14 2000-10-05 Austin Research Institute, The Composition comprising immunogenic virus sized particles (VSP)
DE10121982B4 (de) * 2001-05-05 2008-01-24 Lts Lohmann Therapie-Systeme Ag Nanopartikel aus Protein mit gekoppeltem Apolipoprotein E zur Überwindung der Blut-Hirn-Schranke und Verfahren zu ihrer Herstellung
US6878693B2 (en) 2001-09-28 2005-04-12 Solubest Ltd. Hydrophilic complexes of lipophilic materials and an apparatus and method for their production
WO2003028700A2 (en) * 2001-09-28 2003-04-10 Solubest Ltd. Water soluble nanoparticles of hydrophilic and hydrophobic active materials
US7763663B2 (en) 2001-12-19 2010-07-27 University Of Massachusetts Polysaccharide-containing block copolymer particles and uses thereof
CA2492807A1 (en) * 2002-07-29 2004-03-04 Nanodel Technologies Gmbh Nanoparticles for dna administration to a target organ
US20060228420A1 (en) * 2005-03-15 2006-10-12 Queen Mary & Westfield College Pharmaceutical compositions comprising microparticles for delivery into neurons
CN101432042A (zh) 2005-09-30 2009-05-13 Tti优而美株式会社 用于包封在纳米颗粒中的药物给药的离子电渗疗法的电极组件和使用该组件的离子电渗装置
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
DE102005062440B4 (de) * 2005-12-27 2011-02-24 Lts Lohmann Therapie-Systeme Ag Proteinbasiertes Trägersystem zur Resistenzüberwindung von Tumorzellen
US7848801B2 (en) 2005-12-30 2010-12-07 Tti Ellebeau, Inc. Iontophoretic systems, devices, and methods of delivery of active agents to biological interface
WO2008044705A1 (fr) 2006-10-10 2008-04-17 Tti Ellebeau, Inc. dispositif d'ionophorèse de type dent artificielLE
JP5201763B2 (ja) * 2007-02-28 2013-06-05 昇一 城武 異なる平均粒径サイズの粒子からなる混合微粒子カプセルの製造方法
EP1985286A1 (de) * 2007-04-24 2008-10-29 Biocompatibles UK Limited Mikrokügelchen zur Behandlung von Gehirntumoren
WO2010040173A1 (en) * 2008-10-08 2010-04-15 Commonwealth Scientific And Industrial Research Organisation A method of delivering functional agents across the blood-brain barrier
GB201209517D0 (en) * 2012-05-29 2012-07-11 Univ Birmingham Nanoparticles
CN103623424B (zh) * 2012-08-24 2016-08-03 复旦大学 一种基于聚甲基丙烯酸酯的脑靶向基因递释系统
AU2017360346B2 (en) 2016-11-21 2023-11-23 Eirion Therapeutics, Inc. Transdermal delivery of large agents

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AU3176097A (en) * 1997-06-13 1998-12-30 Medinova Medical Consulting Gmbh Drug targeting system, method of its preparation and its use
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Also Published As

Publication number Publication date
AU4373499A (en) 2000-12-28
JP2003501379A (ja) 2003-01-14
WO2000074658A1 (en) 2000-12-14

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