WO2019034429A1 - Copolymères à blocs multifonction pour dissoudre les plaques d'athérome - Google Patents

Copolymères à blocs multifonction pour dissoudre les plaques d'athérome Download PDF

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Publication number
WO2019034429A1
WO2019034429A1 PCT/EP2018/070868 EP2018070868W WO2019034429A1 WO 2019034429 A1 WO2019034429 A1 WO 2019034429A1 EP 2018070868 W EP2018070868 W EP 2018070868W WO 2019034429 A1 WO2019034429 A1 WO 2019034429A1
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block
polymer block
multifunctional
hydrophilic
acidic polymer
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PCT/EP2018/070868
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German (de)
English (en)
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Helmut Cölfen
Philipp Keckeis
Eliska DRABINOVÁ
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Universität Konstanz
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/40—Polyamides containing oxygen in the form of ether groups
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0233—Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/024—Polyamines containing oxygen in the form of ether bonds in the main chain
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids

Definitions

  • the present invention relates to a multifunctional block copolymer and to a polymeric nanoparticle formed by precipitation polymerization based on the multifunctional block copolymer according to the invention. Furthermore, the present invention relates to a pharmaceutical composition comprising the polymeric nanoparticles and to the use thereof for the absorption of cholesterol and optionally calcium ions from atherosclerotic plaques.
  • Arteriosclerosis is a systemic disease of the arteries, which is characterized by the deposition of blood lipids, thrombi, connective tissue and calcium hydroxyapatite in the vessel walls.
  • the aforementioned deposits which are also referred to as atherosclerotic plaques, eventually lead to narrowing and hardening of the arteries with the consequence of limited or completely interrupted blood flow, which can eventually lead to a heart attack or stroke.
  • arteriosclerosis primarily emphasizes the physiological aging process of the artery, ie its constriction and hardening
  • the term “atherosclerosis” emphasizes the histological changes that underlie arteriosclerosis. Basically, the incidence of arteriosclerosis increases with advancing age.
  • arteriosclerosis can still be treated conservatively by the use of suitable drugs, whereby the medical therapy is usefully accompanied by a change in the arteriosclerosis-related unhealthy lifestyle.
  • drugs are often used which are also administered in the treatment of other cardiovascular diseases. These include, for example, drugs that inhibit blood clotting and thus prevent the formation of thrombi.
  • medicines for lipid metabolism disorders so-called lipid or cholesterol lowering agents, are also used. Since the known in the art for the treatment of atherosclerosis are often associated with side effects as well as existing atherosclerotic plaques often can not or only slightly dissolve, is the search for new and alternative approaches that effective treatment of arteriosclerosis in a drug Allow therapy, as before, unbroken.
  • the present invention provides a multifunctional block copolymer comprising a hydrophilic non-acidic polymer block (A) and further comprising a hydrophilic acidic polymer block (B) and / or a hydrophobic polymer block (C), wherein the hydrophobic polymer block (C) is provided with a steroid or a derivative thereof, and the multifunctional block copolymer at least a structure selected from (A) - (C), (A) - (B) - (C), (A) - (C) - (B) and a combination of the structures (A) - (B) and (A) - (C).
  • the multifunctional block copolymer of the present invention is capable of being in the form of micelles, i. by self-assembly to form polymeric nanoparticles.
  • the latter allow an efficient uptake of atherosclerotic plaque-derived cholesterol molecules and possibly calcium ions in the particle interior.
  • the multifunctional block copolymers according to the invention and the polymeric nanoparticles formed therefrom are free of side effects which are disadvantageous for the patient.
  • the multifunctional block copolymer of the invention comprises at least two different polymer blocks, wherein the hydrophilic non-acidic polymer block (A) is part of each multifunctional block copolymer.
  • the multifunctional block copolymer of the present invention further comprises a hydrophilic acidic polymer block (B) and / or a hydrophobic polymer block (C).
  • the multifunctional block copolymer has at least the structure (A) - (C), (A) - (B) - (C), (A) - (C) - (B) or a combination of the structures (A ) - (B) and (A) - (C).
  • the multifunctional block copolymer of the invention further comprises a hydrophobic polymer block (C * ).
  • C * a hydrophobic polymer block
  • the multifunctional block copolymer of the present invention has the structure (C * ) - (A) - (B) or (C * HA) - (C), or a combination thereof.
  • the hydrophilic non-acidic polymer block (A) effects the dispersion of the above-defined multifunctional block copolymer and the polymeric nanoparticle formed therefrom by self-assembly in an aqueous environment. Accordingly, the hydrophilic non-acidic polymer block (A) must be sufficiently polar to react in aqueous media to be soluble. According to the present invention, the hydrophilic non-acidic polymer block (A) is uncharged and has no acid groups. These are also to be understood as meaning CH-acidic groups which, by the action of strong bases, can likewise be converted into a deprotonated and thus charged form. Otherwise, the hydrophilic non-acidic polymer block (A) according to the invention is not subject to further restrictions.
  • the hydrophilic acidic polymer block (B) is capable of calcium ions from calcium hydroxyapatite CasiPO ⁇ siOH), which, as mentioned above, is a component of the atherosclerotic plaques to adsorb.
  • the hydrophilic acidic polymer block (B) necessarily has acid groups, which are preferably carboxylic acid groups, i. Carboxy groups -COOH.
  • the hydrophilic acidic polymer block (B) is not limited to the presence of carboxy groups.
  • the acid groups may also be sulfonic acid groups, i. Hydroxysul- fonyl -SO2OH act.
  • phosphoric acid groups - OPO (OH) 2 and phosphonic acid groups -PO (OH) 2 or derivatives thereof are also suitable, and also chelating groups, such as ethylenediaminetetraacetic acid (EDTA) or derivatives thereof.
  • EDTA ethylenediaminetetraacetic acid
  • the number of acid groups preferably corresponds to the number of monomers forming the hydrophilic acidic polymer block (B). Otherwise, the hydrophilic acidic polymer block (B) according to the invention is subject to no further restrictions.
  • hydrophobic polymer block (C) also apply in an independent manner to the hydrophobic polymer block (C * ), provided it is present in the multifunctional block copolymer according to the invention, which is indicated by the term "or.”
  • the hydrophobic polymer block (C) or (C *) is able to adsorb cholesterol molecules, which are also part of the atherosclerotic plaques.
  • the hydrophobic polymer block (C) or (G *) is provided with a steroid or a derivative thereof, hereinafter referred to as steroid (derivative).
  • steroid derivative
  • the hydrophobic polymer block (C) or (C * ) necessarily has a suitable functionality, which allows the attachment of the steroid (derivative) s, which may also be a non-covalent attachment.
  • the hydrophobic polymer block (C) or (C *) is sufficiently nonpolar to adsorb cholesterol molecules from the atherosclerotic plaques.
  • the steroid (derivative) which is covalently or non-covalently bound to the backbone of the hydrophobic polymer block (C) or (C * ), is not particularly limited, as long as it is capable of adsorbing cholesterol molecules.
  • the steroid may be functionalized with aliphatic side chains which increase the hydrophobicity of the steroid skeleton.
  • the steroid (derivative) is cholesterol or a derivative thereof, hereinafter referred to as cholesterol (derivative) which, as mentioned above, is functionalized, for example, with aliphatic side chains. Due to the structural similarity, a particularly efficient Van der Waals interaction with the cholesterol molecules to be adsorbed occurs. Another advantage is the commercial availability of cholesterol and its derivatives.
  • the hydrophobic polymer block (C) or (C * ) may be partially or completely grafted with the steroid (derivative).
  • a complete grafting, in which each monomer of the hydrophobic polymer block (C) or (C * ) is provided with the steroid (derivative) is advantageous, since in this way the number of cholesterol molecules, which is the hydrophobic polymer block (C) or (C * ) is able to adsorb increased.
  • the hydrophilic non-acidic polymer block (A) is a polyethylene glycol block and the hydrophilic acidic polymer block (B) and the hydrophobic polymer block (C) or (C *) are each a polypeptide Block.
  • a non-limiting exemplary structural portion of the multifunctional block copolymer of this embodiment having the structure (A) - (B) - (C) is represented by the following formula (I):
  • a corresponding structural section for a multifunctional block copolymer of structure (A) - (C) - (B), (AHB), (A) - (C), (C * ) - (A) - (B) and (C *) - (A) - (C) or their combination can be formulated in an analogous way.
  • the indices a, b and c respectively represent the number of monomers, that is, the number of repeating units of the hydrophilic non-acidic polymer block (A), the hydrophilic acidic polymer block (B) and the hydrophobic polymer block (C)
  • the radical R 'of the hydrophilic acidic polymer block (B) has an acid group
  • the radical R "of the hydrophobic polymer block (C) is functionalized in such a way that it can be provided with a steroid (derivative).
  • the hydrophilic acidic polymer block (B) in this embodiment is preferably, but not limited to, a polyglutamic acid block or a polyaspartic acid block, with a polyglutamic acid block being particularly preferred.
  • the hydrophilic acidic polymer block (B) thus has the necessary acid groups in the radicals R '.
  • the hydrophobic polymer block (C) is preferably, but not limited to, a polylysine block, a polyarginine block or a polyhistidine block, with a polylysine block being particularly preferred.
  • the hydrophobic polymer block (C) has suitable functionalities, which finally with a steroid (derivative) leave.
  • the polypeptide block having the radical R ", in each case 4 to 20, particularly preferably in each case 8 to 15 repeat units, ensures that the multifunctional block copolymers of this embodiment arrange themselves by self-assembly into a polymeric nanoparticle of suitable micelle size.
  • polyfunctional block copolymers based on polyethylene glycol and polypeptides described above are obtainable from commercially available starting materials and can advantageously be prepared by a living ring-opening polymerization.
  • the amino acids used are in the form of their N-carboxyanhydrides, which can be obtained from the respective amino acids, for example by reaction with triphosgene.
  • the amino acids are previously provided with appropriate protective groups.
  • the free carboxy group of glutamic acid is typically protected with a benzyl moiety, while the free amino group of lysine can be protected with a benzyloxycarbonyl moiety.
  • the N-carboxyanhydrides obtained from the thus protected amino acids glutamic acid and lysine are represented by the following formulas (II) and (III):
  • the living ring-opening polymerization can be initiated by the polyethyleneglycol block, in the present case either with the protected glutamic acid-N-carboxyanhydride or with the protected lysine-N- Car oxyanhydride reacts to form the corresponding polypeptide block.
  • a terminal hydroxy group of the polyethylene glycol block is previously replaced with an amino group to enhance its reactivity.
  • the protective groups are finally removed again.
  • a steroid derivative
  • cholesterol derivative
  • the hydrophilic non-acidic polymer block (A), the hydrophilic acidic polymer block (B) and the hydrophobic polymer block (C) or (C *) are each a functionalized polymer (2). oxazoline) block.
  • a non-limiting exemplary structural portion of the multifunctional block copolymer of this embodiment having the structure (A) - (B) - (C) is represented by the following formula (IV):
  • a corresponding structural section for a multifunctional block copolymer of structure (A) - (C) - (B), (AHB), (A) - (C), (C *) - (A) - (B) and (C * ) - (A) - (C) or their combination can be formulated in an analogous manner, the structure (A) - (B) - (C) is basically preferred.
  • Poly (2-oxazolines) are generally considered to be structural isomers of polypeptides and are therefore sometimes referred to as pseudopeptides. Like polypeptides, poly (2-oxazolines) have one amide bond per repeat unit, which is not within the polymer backbone but outside thereof as a side chain. Since the nitrogen atom of the amide bond is tertiary, poly (2-oxazolines) have a particularly high resistance to hydrolysis.
  • indices a, b and c here again represent the number of monomers, ie the number of repeating units of the hydrophilic non-acidic polymer block (A), of the hydrophilic acidic polymer block (B) and of the hydrophobic polymer block (C)
  • Polymer blocks underlying 2-oxazolines are functionalized at the 2-position with the radicals R ⁇ R "or R"'.
  • the radical R 'of the hydrophilic acidic polymer block (B) has an acid group
  • the radical R "of the hydrophobic polymer block (C) is functionalized in such a way that it can be provided with a steroid (derivative) applies to the hydrophobic polymer block (C *), if present
  • the radical R '"of the hydrophilic non-acidic polymer block (A) is such that sufficient water solubility is ensured.
  • the radical R 1 is typically a short-chain alkyl radical, for example but not limited to methyl, ethyl or n-propyl, since the water solubility decreases with increasing chain length, the radical R "is preferred Methyl.
  • the hydrophilic non-acidic polymer block (A), i. the poly (2-oxazoline) block having the radical R '' has from 25 to 100 repeat units
  • a single hydrophobic end group already has an effect on the micellization.
  • the above-described polyfunctional block copolymers based on poly (2-oxazolines) can also be prepared by a living ring-opening polymerization.
  • the polymerization here follows a cationic mechanism, which is initiated, for example, by methyltrifluoromethylsulfonate (methyltriflate, Me-OTf).
  • methyltriflate, Me-OTf methyltriflate
  • the skilled person is aware that ionic polymerizations generally require a termination reaction in order to ultimately obtain the neutral polymerization product.
  • suitable reagents for this purpose.
  • the 2-oxazolines used, in particular for the hydrophilic acidic polymer block (B) and for the hydrophobic polymer block (C) or (C *), preferably have an unsaturated radical R 'or R ", which, after polymerization, still Pre-functionalization is usually eliminated because of side reactions during polymerization, such as the introduction of a living ring-opening polymerization into the hydrophilic acidic polymer block (B) the hydrophobic polymer block (C) or (C * ) is provided with a steroid (derivative), preferably a cholesterol (derivative), examples being the use of 2- (co-alkynyl) -2-oxazolines as monomers for the hydrophilic acidic polymer block (B) and the use of 2 - (& alkenyl) -2-oxazolines as monomers for the hydrophobic polymer block (C) or (C * ) g of the 2- (co-alkynyl) -2-oxazolines can be added after polymerization
  • the introduction of the acid group into the hydrophilic acidic polymer block (B) is not limited to a particular reaction scheme.
  • corresponding synthesis routes are known to the person skilled in the art, wherein he routinely adapts the reaction conditions to the respective starting materials.
  • yl-2-oxazolines can be used as monomers for the hydrophobic polymer block (C) or (C *), for example, 2-nonyl-2-oxazoline, 2-heptadecyl-2-oxazoiin or 2 - ((8Z, 1 1Z) -heptadeca-8,1 1 -dien-1-yl) -2-oxazoline (hereinafter abbreviated to NonOx, HeptadecOx and LinOx), which due to their high hydrocarbon content, are sufficiently hydrophobic to noncovalently bind the steroid (derivative), preferably the cholesterol (derivative).
  • the multifunctional block copolymer comprises a hydrophilic non-acidic polymer block (A) and further comprises a hydrophilic acidic polymer block (B) and / or a hydrophobic polymer block (D), the hydrophilic non-acidic polymer block (A) in that the hydrophilic acidic polymer block (B) and the hydrophobic polymer block (D) are each a functionalized poly (2-oxazoline) block, the hydrophobic polymer block (D) is provided with an unbranched hydrocarbon radical of 8 to 20 carbon atoms and the multifunctional block copolymer at least one structure selected from (A) - (D), (A) - (B) - (D), (A) - (D) - (B) and a combination of the structures (A) - (B) and (A) - (D).
  • each monomer of the hydrophobic polymer block (D) may have an unbranched hydrocarbon radical of 8 to 20, preferably 9 to 18, carbon atoms, but this is not absolutely necessary according to the present invention.
  • the unbranched hydrocarbon radical may in each case be an alkyl, alkenyl and / or alkynyl radical, wherein in the case of an unsaturated hydrocarbon radical this is not restricted to a single double bond or to a single triple bond.
  • Nonyl, heptadecyl and (8Z.11Z) - heptadeca-8,11-dien-1-yl are mentioned here by way of example as hydrocarbon radicals.
  • this is 2-nonyl-2-oxazoline, 2-heptadecyl-2-oxazoline and 2 - ((8Z, 11Z) -heptadeca-8, 11-dien-1-yl) -2-oxazoline.
  • the functionalization of the other poly (2-oxazoline) blocks in this independent embodiment ie, the functionalization of the hydrophilic non-acidic polymer block (A) and the hydrophilic acidic polymer block (B), the above statements apply in connection with the others - ren on poly (2-oxazoline) blocks based multifunctional block copolymers analog.
  • the present invention relates to a polymeric nanoparticle which is formed from the multifunctional block copolymer according to the invention by self-assembly.
  • the specific molecular structure of the multifunctional block copolymer according to the invention allows its arrangement in the form of micelles, ie in the form of polymeric nanoparticles by self-assembly.
  • the polymeric nanoparticle according to the invention is composed at least of a multifunctional block copolymer of the structure (A) - (C), (A) - (B) - (C), (A) - (C) - (B) or of a combination of the structures ( A) - (B) and (A) - (C) formed, wherein in the latter case, the polymeric nanoparticles either both structures (A) - (B) and (A) - (C) includes or in each case in the form of separate nanoparticles the structures (A) - (B) and (A) - (C) is present.
  • a hydrophobic polymer block (C *) may in each case be bonded to the hydrophilic non-acidic polymer block (A).
  • the hydrophobic polymer block (C) forms the core of the polymeric nanoparticle and, like the hydrophilic non-acidic polymer block (A), is for the Formation of the micellar structure of the polymeric nanoparticle responsible.
  • the hydrophilic non-acidic polymer block (A) ensures the stabilization of the polymeric nanoparticle in an aqueous environment, which ultimately results in the obtainment of polymeric nanoparticle dispersions.
  • the polymeric nanoparticle according to the invention thus has a core-shell structure, wherein the core of the polymeric nanoparticle is formed by the hydrophobic polymer block (C) and, if present, by the hydrophobic polymer block (C *), while the hydrophilic non-acidic po - lymerblock (A) forms the shell of the polymeric nanoparticle.
  • Fig. 1 shows a schematic representation of the core-shell structure of a polymeric nanoparticle formed from multifunctional Block copolymers of structure (A) - (C)
  • Fig. 2 shows a schematic representation of the core-shell structure of a polymeric nanoparticle formed from multifunctional block copolymers of structure (AHB) - (C) shows.
  • the polymeric nanoparticle according to the invention is capable of absorbing cholesterol molecules and optionally calcium ions.
  • Ambient cholesterol molecules are transported into the core of the polymeric nanoparticle, where they are adsorbed to the steroid skeleton which is grafted to the hydrophobic polymer block (C) or (C *), respectively.
  • the cholesterol molecules can also adsorb to the aliphatic side chains of a suitably functionalized steroid skeleton.
  • calcium ions bound in the form of calcium hydroxyapatite are adsorbed in the intermediate shell formed by the hydrophilic acidic polymer block (B) if present.
  • multifunctional block copolymers of structure (A) - (B) are double hydrophilic block copolymers, which are initially completely dissolved in an aqueous environment. By dissolving out calcium ions from the hydroxyapatite, these multifunctional block copolymers are finally present as multivalent ions, whereby the hydrophilic acidic polymer blocks (B) are non-covalently crosslinked with one another. This in turn leads to the formation of polymeric nanoparticles with a core-shell structure, wherein the hydrophilic acidic polymer blocks (B) with the bound calcium ions lie inside the micelles.
  • the polymeric nanoparticle according to the invention thus permits the uptake of cholesterol molecules and optionally calcium ions from the environment.
  • the polymeric nanoparticle is thus suitable for dissolving atherosclerotic plaques.
  • the polyfunctional nanoparticles are adapted to the composition of the atherosclerotic plaques.
  • the polymeric nanoparticle according to the invention may include either both structures (A) - (B) and (A) - (C) or each in the form of separate nanoparticles having the structures (A) - (B) or (A) - (C) are present. If the polymeric nanoparticle is formed from a multifunctional block copolymer of both structure (A) - (B) and structure (A) - (C), by adjusting the mixing ratio, the affinity of the polymeric nanoparticle for calcium ions and cholesterol molecules can be targeted being controlled.
  • the multifunctional block copolymers according to the invention and the polymeric nanoparticles formed therefrom by self-assembly can generally be analyzed with the aid of methods known to one skilled in the art in polymer and colloid chemistry.
  • the molecular weight distribution of the multifunctional block copolymers can be determined, for example, by gel permeation chromatography, which is typically carried out in tetrahydrofuran against a polystyrene standard.
  • optical methods such as dynamic light scattering and analytical ultracentrifugation
  • the size of the polymeric nanoparticles and their size distributions can be determined.
  • Critical micelle concentration and charge characteristics can be determined, for example, by fluorescence measurements as well as zeta potential measurements.
  • imaging methods such as (cryo) transmission electron microscopy or atomic force microscopy, can be used to characterize the polymeric nanoparticles.
  • the size of the polymeric nanoparticle is not subject to any limitations in accordance with the invention. Typical values for this are in the range of 10 to 1000 nm, but without being limited thereto. Depending on the composition of the multifunctional block copolymers forming the polymeric nanoparticles, particle sizes in the micrometer range are also possible.
  • the polymeric nanoparticle according to the invention preferably has a particle size in the range from 20 to 500 nm. This will ensure that the cholesterol Molecules can penetrate relatively quickly into the core of the polymeric nanoparticle, where they are finally adsorbed to the grafted steroid (derivative) s.
  • the multifunctional block copolymer comprises the hydrophobic polymer block (D) instead of the hydrophobic polymer block (C).
  • the polymeric Nanoteiichen from a multifunctional block copolymer of structure (A) - (D), (A) - (B) - (D), (A) - (D) - (B) or from a combination of structures ( A) - (B) and (A) - (D) formed, wherein in the latter case, the polymeric Nanoteiichen either both structures (A) - (B) and (A) - (D) includes or in each case in the form of separate Nanoteiichen with the structures (A) - (B) and (A) - (D) is present.
  • the present invention relates to a pharmaceutical composition comprising the polymeric nanoparticles according to the invention.
  • the pharmaceutical composition may also comprise one or more pharmaceutically acceptable excipients which in particular serve to stabilize the polymeric nanoparticle under physiological conditions.
  • the release of the polymeric nanoparticle in the vicinity of the atherosclerotic plaques can be controlled in a targeted manner by appropriate auxiliaries.
  • auxiliaries it can be ensured by a suitable choice of the auxiliaries that the polymer nanomaterials have a sufficient period of time available to take up cholesterol moieties and optionally calcium ions from the environment.
  • Those skilled in the art are familiar with such adjuvants as are generally used in other pharmaceutical compositions.
  • the present invention relates to the use of the pharmaceutical composition according to the invention and to a method for the absorption of cholesterol molecules and optionally calcium ions from atherosclerotic plaques of an individual or patient, in particular of a human.
  • the present invention also relates to the pharmaceutical composition according to the invention. for use in the uptake of cholesterol molecules and optionally calcium ions from atherosclerotic plaques of an individual or a patient, in particular of a human.
  • the pharmaceutical composition can be used, for example, as a medicine, which is administered orally in the simplest case. After taking up the cholesterol molecules and optionally the calcium ions, the polymeric nanoparticles can be excreted in the urine.
  • the use of the pharmaceutical composition according to the invention in the context of a blood wash (Rheopherese) is conceivable.
  • the present invention represents a novel approach that allows efficient resolution of atherosclerotic plaques. This is made possible by the inclusion of cholesterol molecules and possibly calcium ions in the interior of a polymer nanoparticle formed from multifunctional block copolymers.
  • the absorption properties of the polymeric nanoparticle can be controlled in a controlled manner and thus individually adapted to the nature of the atherosclerotic plaques. This is especially true when the polymeric nanoparticle is formed from a multifunctional block copolymer of structure (A) - (B) and (A) - (C).
  • a pharmaceutical composition comprising the polymeric nanoparticle according to the invention, which itself is pharmacologically and toxicologically inert, can thus be used for the effective treatment of arteriosclerosis.
  • the figures show:
  • Fig. 1 shows a schematic representation of the core-shell structure of a polymeric nanoparticle according to the invention, which is formed from multifunctional block copolymers of structure (A) - (C), wherein the shell of the hydrophilic non-acidic polymer block (A) and the core hydrophobic polymer block (C) correspond. Further, uptake of cholesterol molecules derived from simulated atherosclerotic plaques is demonstrated by the polymeric nanoparticle.
  • 2 shows a schematic representation of the core-shell structure of a polymeric nanoparticle according to the invention, which is formed from multifunctional block copolymers of the structure (A) - (B) - (C), the shell corresponding to the hydrophilic non-acidic polymer block (FIG.
  • the Swissschaie the hydrophilic acidic polymer block (B) and the core of the hydrophobic polymer block (C) correspond. Furthermore, the uptake of cholesterol molecules as well as Caicium ions, which originate from simulated atherosclerotic plaques, is shown by the polymeric nanoparticles. 3 shows a schematic representation and the chemical structure of the polyethyleneglycol polypeptide-based multifunctional block copolymers of structure (A) - (B) and (A) - (C).
  • Fig. 4 shows a schematic and chemical structure of the poly-2-oxazolines based multifunctional block copolymers of structure (A) - (B), (AMC) and (A) - (B) - (C).
  • Fig. 5 shows the results of the cytotoxicity studies of selected polymeric nanoparticles based on the multifunctional block copolymers of the invention. None of the polymer nanoparticles investigated show a negative influence on the cell viability of the kidney cells under the given conditions or cause cell death.
  • a multifunctional block copolymer of the structure (A) - (C) based on polyethylene glycol polypeptide ( Figure 3) and the composition mPEGn3-b-PLys, 2 (Chol) 2.4 is organized in the aqueous system (0.5 mg / mL ) Micellar to polymeric nanoparticles with hydrophobic core and hydrophilic shell.
  • the particle size is about 50 nm at a critical micelle concentration of 10 "6 ⁇ 5 M and a slightly positive surface charge of 1, 03 mV.
  • the polymeric nanoparticles thus formed is absorbed on average 3.6 cholesterol molecules per polymer chain (18 wt .-%) of a dedicated test system ( Figure 1)
  • the particle size increases to about 240 nm.
  • M GPC in THF M 1 H NMR Complex Analysis.
  • M DLS intensity weighted diameter.
  • Table A herein shows an exemplary selection of polyethyleneglycol polypeptide-based multifunctional block copolymers of structure (A) - (C) and structure (C *) - (A) - (C), their structural characterization and their capacity, specific amounts of cholesterol to absorb.
  • Example 2 A multifunctional block copolymer of structure (A) - (C) based on poly-2-oxazolines ( Figure 4) and the composition PMeOx46-b-PBuOxe (Chol) o, 8 is organized in the aqueous system (0.5 mg / mL ) Micellar to polymeric nanoparticles with hydrophobic core and hydrophilic shell.
  • the particle size is about 21 nm at a critical micelle concentration of 18 mg / L (10 "5 x 5 M) and a positive surface charge of 2.0 mV.
  • the polymeric nanoparticle thus formed absorbs an average of 3.9 cholesterol molecules per polymer chain (23, FIG. 5% by weight) from a test system provided for this purpose (FIG. 1). [0008] When taking up the cholesterol molecules, there is no significant change in the particle size.
  • Table B herein shows an exemplary selection of poly-2-oxazolines-based multifunctional block copolymers of structure (A) - (C), structure (C * ) - (A) - (C) and structure (A) - (B ) - (C), their structural characterization and their capacity to absorb certain levels of cholesterol.
  • Example 3 A multi-functional block copolymer of the structure (A) - (B) - (C) based on poly-2-oxazolines and the composition P eOx 6 ob PPynOx7,5 (COO ') 2, 3- (Fig.
  • b- PBuOxii, 5 (Chol) 0 , 9 organizes micellar in the aqueous system (0.5 mg / mL) into polymeric nanoparticles with a hydrophobic core, a negatively charged intermediate shell, and a hydrophilic shell, with a particle size of about 20 nm at a critical level Micelle concentration of 16 mg / L (10 5 x 7 M) and a negative surface charge of -12.0 mV.
  • the resulting polymeric nanoparticle absorbs on average 0.7 cholesterol molecules per polymer chain (2.1 wt%) a test system provided therefor ( Figure 2). There is no significant change in particle size upon uptake of the cholesterol molecules.
  • Double hydrophilic block copolymers of a polyethylene glycol block as hydrophilic non-acidic polymer block (A) and a polyaspartic acid block or a polyglutamic acid block as a hydrophilic acidic polymer block (B) show in a titration experiment to determine the uptake of calcium ions in Results listed in Table C:
  • mPEGii3-PAsp33 0.60 Ca 2+ / COO- mPEGii 3 -PGIuii 0.25 Ca 2+ / COO-
  • Polyethylene glycol methyl ether (mPEG) was heated at 80 ° C under reduced pressure to remove any absorbed water.
  • mPEG dried polyethylene glycol methyl ether
  • triphenylphosphine (3.94 g, 15 mmol)
  • phthalimide 2.2 g, 15 mmol
  • the reaction mixture was stirred for seven days at room temperature under a nitrogen atmosphere.
  • the product was extracted with dichloromethane, the organic phase dried with anhydrous magnesium sulfate and removed on a rotary evaporator. The residue was taken up in water and washed twice with diethyl ether. The water was removed and the crude product was dissolved in dichloromethane at pH 10 and precipitated from diethyl ether. The product was a colorless powder (21, 07 g, 4.2 mmol, 86%).
  • N-Carboxyanhydride (NCA) Monomers a) Synthesis of ⁇ -Benzyl-L-Glutamic Acid-N-Carboxyanhydride (BzGlu-NCA)
  • ⁇ -methyl-L-glutamate (15.0 g, 77.6 mmol) was initially introduced and alternately evacuated and sparged with nitrogen.
  • the solid was suspended in 350 mL of anhydrous THF.
  • Triphosgene (7.21 g, 31.0 mmol, 1.2 eq.) was added and heated to 50 ° C. After about an hour, the suspension cleared completely.
  • the resulting hydrogen chloride gas was neutralized directly via a bubble counter in saturated NaOH solution. After four hours of reaction time, nitrogen was passed through the solution to drive off excess phosgene.
  • the transparent solution was concentrated to about 80 ml and precipitated slowly from 600 ml of n-hexane.
  • PEG-b-PLys 750-820 mg, 0.073-0.136 mmol
  • triethylamine 5 eq per lysine monomer
  • cholesterol chloroformate 4 eq per lysine monomer
  • the reaction mixture was filtered and the solvent removed under reduced pressure.
  • the residue was dissolved in 50-70 ml of water and extracted with dichloromethane (5 times 30 ml).
  • the combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed.
  • the crude product was dissolved in small amounts of dichloromethane for additional purification and precipitated from diethyl ether. After filtration, 450-780 mg (60-75%) of a colorless solid were obtained.
  • FT-IR max / cm 1 841, 960, 1059, 1100, 1240, 1278, 1343, 1465, 1530, 1650, 2875, 3288.
  • 6-Bromohexanoic acid (3.0 g, 15.4 mmol) and sodium azide (2.0 g, 30.8 mmol) were dissolved in 10 mL of anhydrous DMF under a nitrogen atmosphere and stirred at 85 ° C for three hours. After an additional 15 hours reaction time at room temperature, the reaction mixture was diluted with dichloromethane and washed with 1N HCl solution. The organic phase was dried over sodium sulfate and removed under reduced pressure. A colorless viscous liquid was obtained (1.93 g, 80%).
  • ESI-S m / z calculates 137.08; found 137.08 + H + .
  • the block copolymers were polymerized in a synthesis microwave. All components were added in a nitrogen atmosphere glove box. In one When the microwave oven was heated, the initiator methyltrifluoromethyl sulphonate (MeOTf) and the corresponding monomers of predetermined stoichiometric composition, as indicated in Table G, were reacted in 6 ml each of anhydrous acetonitrile for 40 minutes at 140.degree. After cooling to room temperature, the further monomer in the glove box was added and polymerized for a further 40 minutes at 140 ° C in the microwave. It was optionally repeated with a third monomer.
  • MeOTf methyltrifluoromethyl sulphonate
  • ESI-S calculates 309.54; found 309.4 + H + . Elemental analysis calculates 4.53% H, 77.61% C, 12.70% N; found 4.66% H, 77.84% C, 12.08% N.
  • the monomer 2 - ((8Z, 11Z) -heptadeca-8,11-dien-1-yl) -2-oxazoline was prepared by a three-step synthesis. The respective steps and the purification were carried out as follows:
  • N-hydroxysuccinimide (6.57 g, 57.09 mmol) was combined with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) (8.20 g, 42.82 mmol)
  • EDAC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • Nitrogen atmosphere dissolved in 180 ml_ of dry dichloromethane.
  • linoleic acid (10.15 g, 36.19 mmol)
  • the reaction mixture was stirred for 20 hours at room temperature.
  • the solvent was then removed and the residue was taken up in 1000 ml of diethyl ether and washed with 400 ml of deionized water (10: 4 v / v).
  • the aqueous phase was extracted twice with 300 ml of diethyl ether, the combined organic phases were dried over sodium sulfate and the solvent was removed. Due to an incomplete reaction of the starting materials, the reaction was repeated.
  • the intermediate from the first batch was added to a solution of N-hydroxysuccinimide (3.68 g, 31.97 mmol) and EDAC (4.60 g, 24.02 mmol) in 100 mL of dry dichloromethane, and the reaction was allowed to proceed Stirred for 41 hours at room temperature. After removal of the solvent, the residue was taken up in a mixture of diethyl ether and deionized water.
  • aqueous phase was extracted three times with 300 ml of Diethyl ether, and the combined organic phases were then dried over sodium sulfate. After removal of the solvent, a colorless oil was obtained (12.67 g, 33.56 mmol, 92.73%).
  • N- (2-chloroethyl) linoleoylamide (10.00 g, 29.24 mmol) was dissolved in 20 mL of dry methanol and heated to 70 ° C. Subsequently, 20 mL of a freshly prepared solution of KOH in methanol (1.77 M) were added dropwise. The reaction was stirred at 70 ° C for 19 hours and then the precipitated salt was filtered off and the solvent was removed under reduced pressure. The resulting yellowish solid was purified over a basic silica gel column obtained by NaOH-MeOH solution. The eluent used was n-hexane. After combining the purified fractions and removing the solvent, a colorless transparent oil was obtained (5.62 g, 18.39 mmol, 62.89%).
  • amphiphilic block copolymers based on 2-methyl-2-oxazoline and 2-nonyl-2-oxazoline, 2-heptadecyl-2-oxazoline or 2 - ((8Z, 1 1Z) - heptadeca-8, 11 - dien-1-yl) -2-oxazoline were obtained by two different methods: (1) using the Schlenk technique, using an oil bath as the heat source (oil bath method); and (2) using a microwave as the heat source , wherein the reactants were filled in a glove box in the reactor (microwave method).
  • the two above-mentioned methods are based on synthetic routes which have been described in the prior art for the block copolymerization of short-chain 2-alkyl-2-oxazolines using an oil bath or a micelle.
  • the block copolymerization was carried out using the Schlenk technique in an oil bath.
  • 2-methyl-2-oxazoline 25-60 eq.
  • 5 ml of dry acetonitrile were placed in a heated flask under a nitrogen atmosphere.
  • methyl trifluoromethyl sulfonate (1 eq., 0.12 mmol)
  • the solution was stirred for 24 hours at 75 ° C.
  • the second 2-oxazoline monomer (3-9 eq.) was added as indicated in Table J.
  • the reaction mixture was again stirred for 24 hours at 75 ° C, the reaction was completed by the addition of ethanolamine or piperidine in excess.
  • the aqueous dispersions were then freeze-dried and the polymers were obtained as a colorless powder.
  • the block copolymerization was carried out in each case in a microwave reactor (10 ml). The temperature was controlled by an IR thermostat. The reactants were filled into the reactor in a glovebox, which allowed the reaction to proceed under a nitrogen atmosphere.
  • 2-methyl-2-oxazoline 25-60 eq.
  • 3 mL of dry acetonitrile were placed in a heated microwave reactor. After addition of methyl trifluoromethylsulfonate (1 eq., 0.12 mmol), the solution was heated to 140 ° C within five minutes in the microwool and then stirred at 140 ° C for 45 minutes.
  • Maldi-TOF MS Am 85.1 (MeOx), 197.3 (NonOx).

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Abstract

La présente invention concerne un copolymère à blocs multifonction comprenant un bloc polymère (A) non-acide hydrophile et en outre un bloc polymère (B) acide hydrophile et/ou un bloc polymère (C) hydrophobe, le bloc polymère (C) hydrophobe étant pourvu d'un stéroïde ou d'un dérivé de celui-ci et le copolymère à blocs multifonction présentant au moins la structure (A)-(C), (A)-(B)-(C), (A)-(C)-(B) ou une combinaison des structures (A)-(B) et (A)-(C). La présente invention concerne en outre une nanoparticule polymère formée par auto-assemblage, sur la base du copolymère à blocs multifonction selon l'invention, une composition pharmaceutique comprenant la nanoparticule polymère ainsi que son utilisation afin d'absorber les molécules de cholestérol et, le cas échéant, les ions calcium issus des plaques d'athérome.
PCT/EP2018/070868 2017-08-14 2018-08-01 Copolymères à blocs multifonction pour dissoudre les plaques d'athérome WO2019034429A1 (fr)

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US3574784A (en) * 1968-03-28 1971-04-13 Allied Chem Carbon-nitrogen backbone block copolymers as antisoilants
US5233020A (en) * 1989-01-13 1993-08-03 Henkel Kommanditgesellschaft Auf Aktien Paint binders
WO2011058776A1 (fr) * 2009-11-12 2011-05-19 独立行政法人科学技術振興機構 Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci
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US5233020A (en) * 1989-01-13 1993-08-03 Henkel Kommanditgesellschaft Auf Aktien Paint binders
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WO2011058776A1 (fr) * 2009-11-12 2011-05-19 独立行政法人科学技術振興機構 Copolymère séquencé, corps composite copolymère séquencé - complexe métallique, et support de structure creuse utilisant ceux-ci
RU2419418C1 (ru) * 2009-11-16 2011-05-27 Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" (ФГУП "ГНЦ "НИОПИК") Состав для удаления содержимого из атеросклеротических отложений в артериях человека

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