EP1993609A2 - Nanoparticules chargées d'agent actif, à base de protéines hydrophiles - Google Patents

Nanoparticules chargées d'agent actif, à base de protéines hydrophiles

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Publication number
EP1993609A2
EP1993609A2 EP07711691A EP07711691A EP1993609A2 EP 1993609 A2 EP1993609 A2 EP 1993609A2 EP 07711691 A EP07711691 A EP 07711691A EP 07711691 A EP07711691 A EP 07711691A EP 1993609 A2 EP1993609 A2 EP 1993609A2
Authority
EP
European Patent Office
Prior art keywords
nanoparticles
hydrophilic
proteins
group
protein
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Withdrawn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
EP07711691A
Other languages
German (de)
English (en)
Inventor
Jörg KREUTER
Klaus Langer
Kerstin Michaelis
Telli Hekmatara
Sebastian Dreis
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.)
LTS Lohmann Therapie Systeme AG
Original Assignee
LTS Lohmann Therapie Systeme AG
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 LTS Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Publication of EP1993609A2 publication Critical patent/EP1993609A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to active ingredient-loaded nanoparticles based on a hydrophilic protein or a combination of hydrophilic proteins in which functional proteins or peptide fragments are bound to the nanoparticles via polyethylene glycol- ⁇ -maleimide-.omega.-NHS ester.
  • the invention relates to active ingredient-loaded nanoparticles based on at least one hydrophilic protein, in which functional proteins or peptide fragments, preferably an apolipoprotein, are bound to the nanoparticles via polyethylene glycol- ⁇ -maleimide-.omega.-NHS ester to form the pharmaceutically or biologically active substance to transport the blood-brain barrier.
  • nanoparticles particles having a size between 10 nm and 1000 nm of artificial or natural macromolecular substances to which drugs or other biologically active material may be covalently, ionically or adsorptively bound or in which these substances may be incorporated.
  • hydrophilic drugs which themselves can not cross the blood-brain barrier, across this barrier, so that these hydrophilic drugs can be therapeutically effective in the central nervous system (CNS).
  • CNS central nervous system
  • a number of drugs by means of polybutylcyanoacrylate nanoparticles 80 (Tween ® 80) were coated or other surfactants with polysorbate be transported across the blood-brain barrier and a significant pharmacological effect cause by their action in the central nervous system.
  • Dalargin, an endorphin hexapeptide, loperamide and tubocuarine, the two NMDA receptor antagonists MRZ 2/576 and MRZ 2/596 from Merz, Frankfurt, as well as the antineoplastic active substance can be examples of drugs administered with such polybutyl cyanoacrylate nanoparticles Called doxorubicin.
  • the mechanism of transport of these nanoparticles across the blood-brain barrier may be due to the fact that
  • Apolipoprotein E is adsorbed by the coating of polysorbate 80 from the nanoparticles. As a result, these particles are likely to fool lipoprotein particles, which are recognized and bound by receptors of the brain capillary endothelial cells, which provide the lipid supply to the brain.
  • Nanoparticles proposed to the biotinylated apolipoprotein E via an avidin-biotin system or a
  • HSA nanoparticles can transport adsorptively or covalently bound drugs incorporated into the albumin particle matrix after intravenous injection across the blood-brain barrier (BBB). In this way, drugs that otherwise do not overcome this barrier for biochemical, chemical or physicochemical reasons, a pharmacological and therapeutic use in the CNS are supplied.
  • BBB blood-brain barrier
  • particulate systems comprising an avidin-biotin system tend to agglomerate upon prolonged storage, thereby increasing the average particle size and adversely affecting the efficiency of the particles.
  • the present invention therefore an object of the invention to provide nanoparticles with which drugs that can not overcome the blood-brain barrier for biochemical, chemical or physicochemical reasons, the CNS can be supplied without these nanoparticles have the disadvantages of the polybutyl cyanoacrylate nanoparticles known from the prior art and of the HSA nanoparticles comprising an avidin-biotin system.
  • Nanopartik ⁇ l based on a hydrophilic protein or a combination of hydrophilic proteins having at least one pharmacologically acceptable and / or biologically active ingredient and to which an apolipoprotein as a functional protein on polyethylene glycol- ⁇ -maleimide- ⁇ -NHS ester is bound.
  • the hydrophilic protein or at least one of the hydrophilic proteins on which the nanoparticles of the invention are based preferably comes from the group of proteins comprising serum albumins, gelatin A, gelatin B and casein. Particularly preferred are hydrophilic proteins of human origin. Very particularly preferred nanoparticles are based on human serum albumin.
  • the bifunctional polyethylene glycol- ⁇ -maleimide- ⁇ -NHS esters have a maleimide group and an N-hydroxy-succinimide ester, between which there is a polyethylene glycol chain of defined length.
  • the functional protein or peptide fragment is coupled to the hydrophilic protein via polyethylene glycol- ⁇ -maleimide- ⁇ -NHS ester having a polyethylene glycol chain having an average molecular weight of 3400 Da or 5000 Da.
  • the apolipoprotein bound via the polyethylene glycol- ⁇ -maleimide- ⁇ -NHS ester to the hydrophilic protein is preferably selected from the group consisting of Apolipoprotein E, apolipoprotein B (ApoB) and apolipoprotein Al (ApoAl) exists.
  • the functional protein is not an apolipoprotein but is selected from the group of proteins consisting of antibodies, enzymes and peptide hormones.
  • the present invention therefore relates to active substance-loaded nanoparticles based on a hydrophilic protein or a combination of hydrophilic proteins, which are distinguished by the fact that the nanoparticles comprise at least one functional protein or peptide fragment which comprises polyethylene glycol- ⁇ -maleimide-.omega.-NHS ester is bound to the hydrophilic protein or hydrophilic proteins.
  • the loading of the nanoparticles with the substance to be transported can be achieved by adsorption of the active substance to the nanoparticles, incorporation of the active substance into the nanoparticles
  • Nanoparticles or by covalent or complexing bond via reactive groups.
  • the nanoparticles according to the invention can be loaded with virtually any desired active substance / pharmaceutical substance.
  • the nanoparticles are loaded with drugs that can not overcome the blood-brain barrier itself.
  • Particularly preferred active ingredients come from the groups of cytostatics, antibiotics, antiviral agents and drugs acting against neurological disorders, for example from the group comprising analgesics, nootropics, antiepileptics, sedatives, psychotropic drugs, pituitary hormones, hypothalamic hormones, other regulatory peptides and their inhibitors, this list being by no means exhaustive.
  • the active ingredient is selected from the group comprising dalargin, loperamide, tubocuarine and doxorubicin.
  • the nanoparticles according to the invention have the advantage that it is possible to dispense with the potentially side-effecting avidin-biotin system in order to couple the functional proteins or their peptide fragments to the hydrophilic protein of the particles.
  • the nanoparticles according to the invention are preferably prepared by first converting an aqueous solution of the hydrophilic protein or the hydrophilic proteins into nanoparticles by a desolvation process and subsequently stabilizing these by cross-linking.
  • the desolvation from the aqueous solvent is preferably carried out by the addition of ethanol.
  • desolvation is also possible by the addition of other water-miscible non-solvents for hydrophilic proteins such as acetone, isopropanol or methanol.
  • gelatin as starting protein was desolvated successfully by addition of acetone.
  • structure-forming salts such as magnesium sulfate or ammonium sulfate is possible.
  • Suitable crosslinkers for stabilizing the nanoparticles are bifunctional aldehydes, preferably glutaraldehyde, and also formaldehyde.
  • crosslinking of the nanoparticle matrix by thermal processes is possible. Stable nanoparticle systems were obtained at 60 0 C for periods of more than 25 hours or 7O 0 C for periods of more than 2 hours.
  • the functional groups (amino groups, carboxyl groups, hydroxyl groups) located on the surface of the stabilized nanoparticles can be used for the direct covalent conjugation of apolipoproteins. These functional groups can be compared via heterobifunctional "spacers" that have a reactivity towards both
  • Amino groups as well as free thiol groups have to be connected to an apolipoprotein in the previously free thiol groups have been introduced.
  • the amino groups of the particle surface are reacted with the heterobifunctional polyethylene glycol (PEG) -based crosslinker polyethylene glycol- ⁇ -maleimide-.omega.-NHS ester.
  • PEG polyethylene glycol
  • the succinimidyl groups of the polyethylene glycol- ⁇ -maleimide- ⁇ -NHS ester react with the
  • PEG groups can be introduced on the particle surface, which in turn have maleimide groups on the other chain end, which can react with a thiolated substance to form a thioether.
  • the polyethylene glycol chain of the polyethylene preferred for the preparation of the nanoparticles according to the invention Glycol- ⁇ -maleimide- ⁇ -NHS ester, the polyethylene glycol chain has an average molecular weight of 3400 Da (NHS PEG3400 times).
  • polyethylene glycol- ⁇ -maleimide- ⁇ -NHS ester with shorter or longer polyethylene glycol chains, for example with a polyethylene glycol chain having an average molecular weight of 5000 daltons.
  • the apolipoprotein, the functional protein or the peptide fragment to be coupled are thiolated by reaction with 2-iminothiolane.
  • the free amino groups of the proteins or peptide fragments are used.
  • the particle systems are cleaned after each reaction step by repeated centrifuging and redispersing in aqueous solution.
  • the protein dissolved in each case is separated after conversion in principle by size exclusion chromatography of low molecular weight reaction products.
  • the preferred method for preparing the drug-loaded, functional proteins or peptide fragments-modified nanoparticles based on a hydrophilic protein or a combination of hydrophilic proteins is characterized in that it comprises the following steps:
  • pharmaceutically or biologically active substances can be incorporated into the particles.
  • the binding of the active ingredient can be both covalent and complexing or adsorptive.
  • the PEG-modified nanoparticles are adsorbed with the drug.
  • the hydrophilic protein or at least one of the hydrophilic proteins is selected from the group of proteins, the serum albumins, gelatin A, gelatin B, casein and similar proteins, or a combination thereof
  • Proteins includes. Most preferably, hydrophilic proteins of human origin are used for the preparation.
  • nanoparticles of the invention of a hydrophilic protein or a combination of hydrophilic proteins that have bound apolipoprotein are pharmaceutically or biologically active agents that would otherwise not cross the blood-brain barrier, particularly hydrophilic drugs, across the blood-brain barrier to transport and to produce pharmacological effects.
  • Preferred active ingredients come from the groups of cytostatics, antibiotics and drugs acting against neurological disorders, for example from the group, the analgesics, nootropics, antiepileptics, sedatives,
  • Psychieuticals pituitary hormones, hypothalamic hormones, other regulatory peptides and their inhibitors.
  • examples of such agents are dalargin, loperamide, tubocuarine, doxorubicin or the like.
  • FIG. 1 Graphical representation of the analgesic effect
  • MPE maximum possible effect
  • the described, drug-loaded and apolipoprotein-modified nanoparticles are suitable for the treatment of a variety of cerebral diseases.
  • the active substances bound to the carrier system are selected according to the respective therapeutic target.
  • the carrier system is particularly suitable for the active ingredients, which have no or no sufficient transition across the blood-brain barrier.
  • active ingredients cytostatics for the treatment of cerebral tumors into consideration, drugs for the therapy of viral infections in the cerebral area, such as HIV infections, but also drugs for the treatment of dementia diseases, to enumerate only a few applications.
  • the invention therefore also relates to the use of the nanoparticles according to the invention for the production of medicaments, in particular the use of Nanoparticles according to the invention, in which the functional protein is an apolipoprotein, for the production of a medicament for the treatment of cerebral diseases or for the treatment of cerebral diseases, since these nanoparticles can be used for the transport of pharmaceutically or biologically active substances across the blood-brain barrier.
  • Desolvation was achieved by dissolving 200 mg of human serum albumin in 2.0 ml of a 10 mM NaCl solution and adjusting the pH of this solution to 8.0. While stirring, 8.0 ml of ethanol were added dropwise to this solution
  • the nanoparticles were stabilized by adding 235 ⁇ l of an 8% glutaraldehyde solution. After an incubation time of 12 h, the nanoparticles were purified by triple centrifugation and redispersion first in purified water and then in PBS buffer (pH 8.0).
  • apolipoprotein For covalent attachment of an apolipoprotein, free thiol groups were first introduced into its structure. For this, 500 ⁇ g of the apolipoprotein were dissolved in 1.0 ml of TEA buffer (pH 8.0), and 2-iminothiolane (Traut's reagent) was added in a 50-fold molar excess. After a reaction time of 12 h at room temperature, the thiolated apolipoprotein was purified by size exclusion chromatography on a dextran desalting column (D-Salt ® Column) and thereby separated low molecular weight reaction products.
  • D-Salt ® Column dextran desalting column
  • thiolated apolipoprotein For the covalent conjugation of the thiolated apolipoprotein to HSA nanoparticles, 25 mg of the PEG-modified HSA nanoparticles were mixed with 500 ⁇ g of the thiolated apolipoprotein and this mixture was incubated for 12 hours at room temperature. Unreacted apolipoprotein was removed after this reaction time by centrifuging and redispersing the nanoparticles. In the final purification step, the apolipoprotein-modified HSA nanoparticles were taken up in 2.6 vol% ethanol.
  • apolipoprotein E In separate reactions, apolipoprotein E, apolipoprotein B and apolipoprotein Al were thiolated and coupled to HSA nanoparticles.
  • Loperamide as an opioid which in dissolved form can not cross the blood-brain barrier (BBB), is a particularly suitable model drug for a corresponding carrier system for overcoming the BBB.
  • a 5 analgesic effect after application of a loperamide-containing preparation provides direct evidence of an accumulation of the substance in the central nervous system and thus for overcoming the BBB.
  • a typical nanoparticulate preparation used in animal studies contained 10.0 mg / ml nanoparticles, 0.7 mg / ml loperamide, and 190 ⁇ g / ml ApoE.
  • compositions of the ready-to-use 5 nanoparticulate preparations (total volume 2.0 ml) for the animal experiments were:
  • analgesic effects shown in FIG. 1 were achieved after intravenous injection using the abovementioned active ingredient loperamide.
  • a loperamide solution was used 0, 7 mg / ml in 2.6 vol .-% ethanol.
  • the free substance loperamide itself shows no analgesic effect due to lack of transport across the blood-brain barrier.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nanoparticules chargées d'agent actif, à base d'une protéine hydrophile ou d'une combinaison de protéines hydrophiles. Selon l'invention, des protéines fonctionnelles ou des fragments de peptides fonctionnels sont liés aux nanoparticules par un polyéthylènglykol-a-maléimid-?-NHS-ester. L'invention porte également sur des procédés pour les réaliser et sur leur utilisation.
EP07711691A 2006-03-14 2007-02-27 Nanoparticules chargées d'agent actif, à base de protéines hydrophiles Withdrawn EP1993609A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006011507A DE102006011507A1 (de) 2006-03-14 2006-03-14 Wirkstoffbeladene Nanopartikel auf Basis hydrophiler Proteine
PCT/EP2007/001675 WO2007104422A2 (fr) 2006-03-14 2007-02-27 Nanoparticules chargées d'agent actif, à base de protéines hydrophiles

Publications (1)

Publication Number Publication Date
EP1993609A2 true EP1993609A2 (fr) 2008-11-26

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EP07711691A Withdrawn EP1993609A2 (fr) 2006-03-14 2007-02-27 Nanoparticules chargées d'agent actif, à base de protéines hydrophiles

Country Status (15)

Country Link
US (1) US20090304720A1 (fr)
EP (1) EP1993609A2 (fr)
JP (1) JP2009529547A (fr)
KR (1) KR20080100376A (fr)
CN (1) CN101443045A (fr)
AU (1) AU2007226816A1 (fr)
BR (1) BRPI0709296A2 (fr)
CA (1) CA2646447A1 (fr)
DE (1) DE102006011507A1 (fr)
IL (1) IL193971A0 (fr)
MX (1) MX2008011428A (fr)
NZ (1) NZ571929A (fr)
RU (1) RU2424819C2 (fr)
WO (1) WO2007104422A2 (fr)
ZA (1) ZA200806998B (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8946200B2 (en) * 2006-11-02 2015-02-03 Southwest Research Institute Pharmaceutically active nanosuspensions
US8404850B2 (en) * 2008-03-13 2013-03-26 Southwest Research Institute Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors
CN102088963A (zh) * 2008-05-06 2011-06-08 葛兰素集团有限公司 生物活性剂的囊封方法
US8722706B2 (en) * 2008-08-15 2014-05-13 Southwest Research Institute Two phase bioactive formulations of bis-quaternary pyridinium oxime sulfonate salts
US8309134B2 (en) * 2008-10-03 2012-11-13 Southwest Research Institute Modified calcium phosphate nanoparticle formation
US9028873B2 (en) * 2010-02-08 2015-05-12 Southwest Research Institute Nanoparticles for drug delivery to the central nervous system
CN102788879B (zh) * 2011-05-20 2015-04-01 常州康卫生物技术有限公司 一种生物检测试剂
CA2949092A1 (fr) * 2014-05-16 2015-11-19 Dana-Farber Cancer Institute, Inc. Particules a base de proteines permettant d'administrer un medicament
EP3215116B1 (fr) * 2014-11-05 2020-09-30 University of the Sciences in Philadelphia Conjugué de gélatine-doxorubicine biodégradable de poids moléculaire élevé
TWI585162B (zh) * 2015-10-29 2017-06-01 行政院原子能委員會核能研究所 奈米顆粒及其製備方法
CN108948152A (zh) * 2017-05-18 2018-12-07 中国科学院上海药物研究所 一种两亲性穿膜肽键合物、其制备方法及用途
CN111505140A (zh) * 2020-04-24 2020-08-07 厦门大学 基于病毒衣壳蛋白纳米结构的化学信号放大倍增器及制备方法和应用
CN114316279B (zh) * 2020-10-09 2023-09-22 南京大学 一种以环糊精为核的星形聚合物及其蛋白/多肽偶联物
CN117838660A (zh) * 2024-03-01 2024-04-09 广东工业大学 一种抗体修饰的抗肿瘤载药人血白蛋白纳米颗粒及其制备方法及应用

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3040121B2 (ja) * 1988-01-12 2000-05-08 ジェネンテク，インコーポレイテッド 増殖因子レセプターの機能を阻害することにより腫瘍細胞を処置する方法
US5216130A (en) * 1990-05-17 1993-06-01 Albany Medical College Complex for in-vivo target localization
US6391343B1 (en) * 1991-01-15 2002-05-21 Hemosphere, Inc. Fibrinogen-coated particles for therapeutic use
US5362718A (en) * 1994-04-18 1994-11-08 American Home Products Corporation Rapamycin hydroxyesters
AU6100296A (en) * 1995-06-06 1996-12-24 Hemosphere, Inc. Protein particles for therapeutic and diagnostic use
US6267958B1 (en) * 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
JP3437685B2 (ja) * 1995-09-12 2003-08-18 株式会社東芝 交直変換装置の制御保護システム
US6210707B1 (en) * 1996-11-12 2001-04-03 The Regents Of The University Of California Methods of forming protein-linked lipidic microparticles, and compositions thereof
US6002008A (en) * 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6288082B1 (en) * 1998-09-29 2001-09-11 American Cyanamid Company Substituted 3-cyanoquinolines
US6297258B1 (en) * 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
US6277983B1 (en) * 2000-09-27 2001-08-21 American Home Products Corporation Regioselective synthesis of rapamycin derivatives
EP1118335A1 (fr) * 2000-01-11 2001-07-25 Aventis Behring GmbH Préparation de conjugués pour le traitement des allergies et maladies autoimmunitaires
US7306801B2 (en) * 2000-05-15 2007-12-11 Health Research, Inc. Methods of therapy for cancers characterized by overexpression of the HER2 receptor protein
JP2004507465A (ja) * 2000-08-11 2004-03-11 ワイス エストロゲン受容体陽性癌腫の治療方法
TWI286074B (en) * 2000-11-15 2007-09-01 Wyeth Corp Pharmaceutical composition containing CCI-779 as an antineoplastic agent
TWI296196B (en) * 2001-04-06 2008-05-01 Wyeth Corp Antineoplastic combinations
TWI233359B (en) * 2001-04-06 2005-06-01 Wyeth Corp Pharmaceutical composition for treating neoplasm
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
ZA200603888B (en) * 2001-06-01 2007-05-30 Wyeth Corp Antineoplastic combinations
UA77200C2 (en) * 2001-08-07 2006-11-15 Wyeth Corp Antineoplastic combination of cci-779 and bkb-569
PT1478648E (pt) * 2002-02-01 2014-07-15 Ariad Pharma Inc Compostos contendo fósforo e suas utilizações
WO2003106622A2 (fr) * 2002-05-30 2003-12-24 The Children's Hospital Of Philadelphia Procedes de traitement de la leucemie lymphoide aigue
WO2004004644A2 (fr) * 2002-07-05 2004-01-15 Beth Israel Deaconess Medical Center Association d'un inhibiteur de cible mammalienne de rapamycine (mtor) et d'un inhibiteur de la tyrosine kinase aux fins du de traitement de neoplasmes
EP1539811A4 (fr) * 2002-09-16 2006-05-24 Elusys Therapeutics Inc Production de molecules bispecifiques au moyen de lieurs de polyethylene glycol
UA83484C2 (uk) * 2003-03-05 2008-07-25 Уайт Спосіб лікування раку грудей комбінацією похідного рапаміцину і інгібітора ароматази - летрозолу, фармацевтична композиція
DE602004004520T2 (de) * 2003-04-22 2007-11-08 Wyeth Antineoplastische zusammensetzungen
US7399865B2 (en) * 2003-09-15 2008-07-15 Wyeth Protein tyrosine kinase enzyme inhibitors
DE102004011776A1 (de) * 2004-03-09 2005-11-03 Lts Lohmann Therapie-Systeme Ag Trägersystem in Form von Nanopartikeln auf Proteinbasis zur zellspezifischen Anreicherung von pharmazeutisch aktiven Wirkstoffen
AR047988A1 (es) * 2004-03-11 2006-03-15 Wyeth Corp Combinaciones antineoplásicas de cci-779 y rituximab
CA2923748C (fr) * 2005-03-21 2017-06-20 The Regents Of The University Of California Nanoparticules magnetiques fonctionnalisees et leurs methodes d'utilisation
CA2606018A1 (fr) * 2005-04-28 2006-11-02 Ventana Medical Systems, Inc. Conjugues de nanoparticules
US20070105887A1 (en) * 2005-11-04 2007-05-10 Wyeth Antineoplastic combinations of temsirolimus and sunitinib malate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007104422A2 *

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WO2007104422A8 (fr) 2007-11-08
US20090304720A1 (en) 2009-12-10
WO2007104422A3 (fr) 2008-03-20
ZA200806998B (en) 2009-07-29
WO2007104422A2 (fr) 2007-09-20
CN101443045A (zh) 2009-05-27
AU2007226816A1 (en) 2007-09-20
MX2008011428A (es) 2008-09-22
KR20080100376A (ko) 2008-11-17
RU2424819C2 (ru) 2011-07-27
NZ571929A (en) 2011-07-29
CA2646447A1 (fr) 2007-09-20
IL193971A0 (en) 2009-09-22
BRPI0709296A2 (pt) 2011-07-05
DE102006011507A1 (de) 2007-09-20
JP2009529547A (ja) 2009-08-20
RU2008140370A (ru) 2010-04-20

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