Particle for delivering drug to heart and / or diaphragm and pharmaceutical composition

Abstract

The main purpose of the present invention is to develop a drug delivery system capable of suitably delivering a drug to the heart and / or the diaphragm. The present invention provides: particles for delivering a drug to the heart and / or the diaphragm, the particles having a boronic acid group as a target directional site; and a pharmaceutical composition or the like comprising said particles for delivering a drug.

Description

Particles and pharmaceutical compositions for drug delivery to the heart and / or diaphragm

[0001] The present invention relates to particles for drug delivery to the heart and / or diaphragm and pharmaceutical compositions containing the particles for drug delivery.

[0002] Various drug delivery systems (DDS) have been developed to efficiently deliver drugs, including liposome and micelle formulations containing drugs (see, for example, Patent Documents 1 and 2).

[0003] In the development of the above-mentioned DDS, in order to achieve highly target-selective drug delivery, targeting moieties (e.g., ligands) that can specifically recognize targets are introduced into drugs or drug transporters to impart targeting properties to them.

[0004] On the other hand, the heart and diaphragm are among the organs with low drug delivery efficiency, and a DDS that can efficiently deliver drugs to these organs is needed. For example, in the treatment of diseases such as Duchenne muscular dystrophy and heart failure, a DDS that can efficiently deliver drugs to the heart is needed.

[0005] WO2019 / 240223WO2013 / 162041

[0006] The main object of the present invention is to develop a DDS that can efficiently deliver drugs to the heart and / or diaphragm.

[0007] The present inventors have discovered that a boronic acid group can function as a targeting moiety in drug delivery to the heart and / or diaphragm, and have completed the present invention. [1] According to one aspect of the present invention, there is provided a particle for drug delivery to the heart and / or diaphragm, which has a boronic acid group as a targeting moiety. [2] The drug delivery particle described in [1] above may contain the boronic acid group in the form of a phenylboronic acid group or a pyridineboronic acid group. [3] The drug delivery particle described in [1] or [2] above may have a particle diameter of 100 nm or less. [4] The drug delivery particle described in any of [1] to [3] above may contain a drug transporter component molecule to which the boronic acid group and a drug are bound. [5] In the drug delivery particle described in [4] above, the drug transporter component molecule may be a linear polymer, a branched polymer, or a graft polymer. [6] The drug delivery particle described in any one of [1] to [3] above may contain a complex of a specific number of drug transporter components and a drug, and the boronic acid group may be bound to at least one of the drug transporter components and the drug. [7] The drug delivery particle described in any one of [1] to [3] above may contain a micelle or vesicle containing the drug transporter components bound to the boronic acid group. [8] The drug delivery particle described in [7] above may further contain a drug, and the drug may be encapsulated in the micelle or vesicle. [9] The drug delivery particle described in any one of [1] to [3] above may contain the drug bound to the boronic acid group.

[10] The drug delivery particle described in any one of [1] to [9] above may be used for the treatment of diseases requiring drug delivery to the heart and / or diaphragm.

[11] According to another aspect of the present invention, a pharmaceutical composition is provided comprising the drug delivery particle described in any one of [1] to

[10] above.

[12] According to another aspect of the present invention, there is provided a use of a boronic acid group for imparting targeting to the heart and / or diaphragm to a drug or drug transporter.

[13] According to another aspect of the present invention, there is provided a use of a boronic acid compound for producing the drug delivery particle according to any one of [1] to

[10] above.

[0008] According to the drug delivery particles of the embodiments of the present invention, the boronic acid group exhibits heart and / or diaphragm-directing property, thereby enabling efficient drug delivery to the heart and / or diaphragm. Although this effect is not intended to limit the present invention, it is presumed that the boronic acid group functions as a ligand that specifically recognizes the cell surface of the heart (specifically, the surfaces of cardiomyocytes and other cells that constitute the heart).

[0009] Figure 5A and 5B are diagrams illustrating the biodistribution of drug delivery particles composed of a hyperbranched polymer having boronic acid groups bonded thereto. Figure 5B is a diagram illustrating the biodistribution of drug delivery particles composed of a graft polymer having boronic acid groups bonded thereto. Figure 5A and 5B are diagrams illustrating the biodistribution of drug delivery particles composed of a graft polymer having boronic acid groups bonded thereto.

[0010] Preferred embodiments of the present invention will be described below, but the present invention is not limited to these embodiments. The embodiments can be combined as appropriate unless such understanding is clearly inappropriate from the context. Furthermore, in this specification, the term "to" indicating a range of values ​​includes the upper and lower limits.

[0011] A. Drug Delivery Particles The drug delivery particles of the present invention are used to deliver drugs to the heart and / or diaphragm. The drug delivery particles contain a boronic acid group (—B(OH)) as a targeting moiety that is directed to the heart and / or diaphragm. ２ )

[0012] The drug delivery particles are typically nanoparticles having a particle size of less than 1 μm, preferably 100 nm or less. The particle size of the drug delivery particles is, for example, 5 nm to 50 nm, and may be 6 nm or more or 8 nm or more, or 40 nm or less, 35 nm or less, or 30 nm or less. When the particle size of the drug delivery particles is within the above range, excretion from the kidney into urine and nonspecific accumulation in organs other than the target can be suppressed. The particle size is the hydrodynamic diameter and can be determined, for example, by dynamic light scattering (DLS) or fluorescence correlation spectroscopy (FCS). In this specification, the drug delivery particles may be any object having the above particle size as the hydrodynamic diameter. Therefore, the drug delivery particles are not limited to spherical shapes and may have any shape. Furthermore, the drug delivery particles may be composed of a single molecule or an aggregate of multiple molecules.

[0013] The drug delivery particle may or may not contain a drug. In one embodiment, the drug delivery particle contains a drug to which a boronic acid group has been introduced (bound). In another embodiment, the drug delivery particle contains a drug transporter (DDS carrier) component molecule to which a boronic acid group has been introduced (bound). The DDS carrier component molecule may constitute a DDS carrier alone, or in combination with a drug, or in combination with a drug. When a DDS carrier is constituted by an assembly of multiple DDS carrier component molecules, only one type of DDS carrier component molecule may be used alone, or two or more types may be used in combination. Furthermore, the DDS carrier component molecule may be bound to a drug.

[0014] The boronic acid group can be introduced into the drug delivery particle in any suitable form as long as the effects of the present invention can be obtained. For example, the drug delivery particle may be prepared by incorporating —B(OH) into an aliphatic hydrocarbon group. ２ The aliphatic boronic acid group and / or aromatic ring to which -B(OH) ２The aromatic hydrocarbon group has an aromatic boronic acid group into which is introduced. Examples of the aliphatic hydrocarbon group include linear or branched alkyl groups, alkenyl groups, and alkynyl groups, which may contain a cyclic structure. The number of carbon atoms in the aliphatic hydrocarbon group is 1 or more, and may be, for example, 24 or less, 12 or less, or 6 or less. The aromatic ring may be an aromatic hydrocarbon ring whose ring constituent atoms are only carbon, or may be an aromatic heterocycle containing a heteroatom as a ring constituent atom. The aromatic ring may be a monocyclic aromatic ring or a polycyclic aromatic ring.

[0015] The aliphatic boronic acid group is, for example, a group represented by the following formula (1): １ -B(OH) ２ (1) (wherein, R １ is a divalent group formed by removing two hydrogen atoms from a straight-chain or branched alkane, alkene, or alkyne, which may contain a cyclic structure.

[0016] The aromatic boronic acid group can be, for example, a group represented by the following formula (2): -Ar-B(OH) ２ (2) (wherein Ar is an aromatic ring).

[0017] Regarding formula (2), specific examples of the aromatic ring include a benzene ring, a pyridine ring, a naphthalene ring, a biphenyl ring, etc. Among these, the aromatic boronic acid group is preferably a phenylboronic acid group in which Ar is a benzene ring or a pyridineboronic acid group in which Ar is a pyridine ring.

[0018] In the benzene ring and pyridine ring, -B(OH) ２ The position number of the carbon to which is bonded (the position number of the carbon having a free valence is assumed to be 1) may be 2, 3, or 4, for example, 3 or 4, preferably 4. In addition, in the pyridine boronic acid group, the position number of the nitrogen in the pyridine ring may be 2, 3, or 4, for example, 2 or 3, preferably 2.

[0019] The aromatic ring may have a substituent at any position on the ring. Examples of the substituent include halogens such as fluorine, chlorine, and bromine, alkyl groups having 1 to 3 carbon atoms (e.g., methyl groups), fluorinated alkyl groups having 1 to 3 carbon atoms (e.g., trifluoromethyl groups), alkoxy groups having 1 to 3 carbon atoms (e.g., methoxy groups), formyl groups, nitro groups, and amino groups. The aliphatic hydrocarbon groups may also have a substituent at any position. Examples of the substituent include halogens such as fluorine, chlorine, and bromine, nitro groups, and amino groups. The number of substituents in the aromatic ring or the aliphatic hydrocarbon group may be 0 to 4, for example, 0 to 2.

[0020] The phenylboronic acid group is, for example, a group represented by the following formula (3): (In formula (3), n1 is an integer of 0 to 4, for example, 0, 1, or 2, and when n1 is 1, F and B(OH) ２ The introduction position of may be ortho, meta, or para.

[0021] The pyridine boronic acid group is, for example, a group represented by the following formula (4): (In formula (4), n2 is an integer of 0 to 3, for example, 0, 1, or 2, and when n2 is 1, F and B(OH) ２ The introduction position of may be ortho, meta, or para.

[0022] A-1. Drug delivery particle comprising a DDS carrier component molecule to which a boronic acid group and a drug are bound. The DDS carrier component molecule to which a boronic acid group and a drug are bound is a conjugate between the DDS carrier component molecule to which a boronic acid group is bound and the drug. Drug delivery particles comprising a drug transporter component to which a boronic acid group and a drug are bound can be composed of the conjugate. The number of DDS carrier component molecules contained in the drug delivery particle may be one.

[0023] Biocompatible polymers are preferably used as DDS carrier constituent molecules. The biocompatible polymer is preferably a hydrophilic polymer. Examples of the hydrophilic polymer include poly(ethylene glycol), poly(saccharide), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylamide), poly(acrylic acid), poly(methacrylamide), poly(methacrylic acid), poly(methacrylic acid ester), poly(acrylic acid ester), poly(amino acid) (e.g., poly(aspartic acid), poly(glutamic acid), poly(serine)), poly(malic acid), and copolymers or derivatives thereof. Among these, poly(ethylene glycol) is preferably used. Various poly(ethylene glycol)s having terminal functional groups are commercially available.

[0024] The polymer may be a linear polymer, a branched polymer (including a dendrimer or dendron), or a graft polymer. By changing the chain length of the linear polymer, the number or length of branches of the branched polymer, or the number or length of graft chains of the graft polymer, a conjugate with a desired particle size can be suitably obtained.

[0025] The molecular weight (Mw) of the linear polymer may be, for example, 100 to 1,000,000, preferably 500 to 100,000, more preferably 1,000 to 50,000, and may be, for example, 3,000 or more, 5,000 or more, or 10,000 or more. The molecular weight of the polymer can be determined, for example, by size exclusion chromatography.

[0026] The number of polymer chains in the branched polymer may be, for example, 2 or more, 5 or more, or 6 or more, and may be, for example, 200 or less, or 50 or less.

[0027] The molecular weight (Mw) of each polymer chain of the branched polymer can be independently, for example, from 100 to 1,000,000, preferably from 500 to 100,000, and more preferably from 1,000 to 50,000. In one embodiment, each polymer chain of the branched polymer can have the same molecular weight as the other polymer chains.

[0028] The molecular weight (Mw) of the branched polymer as a whole may be, for example, 200 to 2,000,000, preferably 1,000 to 200,000, more preferably 2,000 to 100,000, and may be, for example, 3,000 or more, 5,000 or more, or 10,000 or more.

[0029] The boronic acid group and the drug may be attached to any position on the linear polymer and the branched polymer, respectively. The boronic acid group may be attached preferably to the end of at least one polymer chain. The drug may be attached to any position on the polymer chain, or may be attached to the end of the polymer chain. The number of boronic acid groups attached to one molecule of the linear polymer and the branched polymer, respectively, may be, for example, 1 to 200, or 1 to 100. The number of drugs attached to one molecule of the linear polymer and the branched polymer, respectively, may be, for example, 1 to 200, or 1 to 50, or 1 to 10.

[0030] The graft polymer may be a polymer in which a biocompatible polymer is grafted to the side chain of a trunk polymer. The biocompatible polymer is preferably a hydrophilic polymer, specific examples of which are as described above.

[0031] Examples of polymers that constitute the trunk polymer include poly(aspartic acid), poly(glutamic acid), poly(aspartic acid)-poly(glutamic acid) copolymer, poly(amino acids) such as poly(lysine), poly(acrylic acid), poly(vinyl alcohol), chitosan, and poly(vinylamine).

[0032] The number of graft chains possessed by the graft polymer is, for example, 1 or more, preferably 5 or more, and may be 20 or more or 50 or more, and may be, for example, 500 or less, or 100 or less.

[0033] The molecular weight (Mw) of each graft chain of the graft polymer may be independently, for example, 500 to 100,000, preferably 500 to 50,000, and more preferably 1,000 to 20,000. In one embodiment, each graft chain may have the same molecular weight as the others.

[0034] The number of structural units of the trunk polymer (degree of polymerization) may be, for example, 5 to 1000, and preferably 10 to 200. The introduction rate of graft chains (number of introduced graft chains / degree of polymerization of trunk polymer×100) may be, for example, 1% to 100%, 5% to 80%, or 10% to 80%.

[0035] The molecular weight (Mw) of the graft polymer as a whole may be, for example, 500 to 1,000,000, preferably 10,000 to 500,000, and more preferably 20,000 to 200,000.

[0036] The boronic acid group and the drug may each be bound to any position on the graft polymer. The boronic acid group may preferably be bound to the end of the graft chain. The drug may be bound to any position on the graft polymer, and may be bound to the end of the main chain or the end of the graft chain. The number of boronic acid groups bound to one molecule of the graft polymer may be, for example, 1 to 1000, 1 to 100, or 1 to 50. The number of drugs bound to one molecule of the graft polymer may be, for example, 1 to 1000, 1 to 500, or 1 to 100.

[0037] Any appropriate substance can be used as the drug depending on the purpose. The drug can be, for example, a substance having various physiological activities such as cytostatic activity, antitumor activity, immunomodulatory activity, antiviral activity, antibacterial activity, or anti-inflammatory activity. The drug can also be a detection reagent such as a fluorescent dye or a contrast agent, or a cell.

[0038] Specific examples of physiologically active drugs include proteins (e.g., antibodies or functional fragments thereof, enzymes, hormones), nucleic acids (e.g., high molecular weight nucleic acids such as plasmid DNA and mRNA, and low molecular weight nucleic acids such as siRNA, miRNA, antisense nucleic acids, and aptamers), and other physiologically active substances (e.g., antitumor agents, signal transduction inhibitors, antimetabolites, analgesics, anti-inflammatory agents, and antibacterial agents).

[0039] The drug may be a low molecular weight drug (e.g., less than 1 kDa) or a high molecular weight drug, e.g., 1 kDa or more, 5 kDa or more, or 10 kDa or more, e.g., 1000 kDa or less, 200 kDa or less, or 50 kDa or less.

[0040] The binding of a drug to a DDS carrier component molecule can be carried out by any suitable method. For example, a drug can be bound to a DDS carrier component molecule by using a drug having a functional group A and a DDS carrier component molecule having a functional group B capable of binding to functional group A, and reacting functional group A with functional group B. In this case, the functional group A possessed by the drug may be inherent in the drug, or may be bound to the drug via a linker.

[0041] Similarly, the introduction of a boronic acid group into a DDS carrier constituent molecule can be carried out by binding a boronic acid compound having a boronic acid group and another functional group to the DDS carrier constituent molecule directly or via a linker.

[0042] A-2. Drug delivery particles containing drug transporter components bound to boronic acid groups Drug delivery particles containing DDS carrier components bound to boronic acid groups can be, for example, micelles or vesicles containing DDS carrier components bound to boronic acid groups, polyion complexes (PICs) containing DDS carrier components bound to boronic acid groups and drugs, hydrogel particles composed of DDS carrier components bound to boronic acid groups, etc. Examples of drugs include those described in Section A-1.

[0043] A-2-1. Micelles Micelles can be particulate aggregates formed by the aggregation of amphiphilic molecules having hydrophilic and hydrophobic segments. Micelles may encapsulate a drug inside. The drug encapsulated in the micelles may or may not be bound to a DDS carrier component molecule.

[0044] Examples of micelles include micelles formed by arranging block copolymers having a first polymer segment and a second polymer segment having a lower hydrophilicity than the first polymer segment in a generally radial pattern with the second polymer segment facing inward. As shown in Figure 1, a micelle 100 includes, as DDS carrier constituent molecules, a block copolymer 110a having a first polymer segment 112, a second polymer segment 114, and a boronic acid group 116 attached to the end of the first polymer segment 112. Optionally, the micelle 100 may further include a block copolymer 110b having the first polymer segment 112 and the second polymer segment 114, but no boronic acid group attached thereto.

[0045] The number of boronic acid groups introduced per micelle is not limited as long as the effects of the present invention are obtained, and can be appropriately selected depending on the size of the micelle, etc. The number of boronic acid groups introduced is, for example, 1 to 10,000, and may be 5 or more, or 10 or more, or 1,000 or less, 100 or less, or 20 or less.

[0046] The first polymer segment typically comprises a biocompatible hydrophilic polymer. Examples of biocompatible hydrophilic polymers include those described in Section A-1. Among these, polymers that have no charge at physiological pH (pH 7.4) are preferred, nonionic polymers are more preferred, and poly(ethylene glycol) is even more preferred.

[0047] The molecular weight (Mw) of the hydrophilic polymer may be, for example, 1,000 to 100,000, preferably 2,000 to 60,000, more preferably 5,000 to 50,000, and even more preferably 10,000 to 40,000.

[0048] In the illustrated example, the first polymer segment is composed of a linear polymer, but the first polymer segment may also be composed of a branched polymer or a graft polymer. Examples of branched polymers and graft polymers include those described in Section A-1. In the illustrated example, one boronic acid group is bonded per block copolymer molecule, but two or more boronic acid groups may be bonded per block copolymer molecule. The boronic acid group may be bonded, for example, to the main chain or branched chain end, or the side chain or graft chain end of the first polymer segment of the block copolymer. The boronic acid group is preferably located on the outer surface of the micelle. In other words, the micelle preferably contains boronic acid groups exposed on its outer surface.

[0049] The second polymer segment may comprise, for example, a poly(amino acid). Appropriate selection of the side chains of the poly(amino acid) allows for adjustment of micelle stability, drug retention, and other properties. For example, hydrophobic side chains in the poly(amino acid) may result in hydrophobic interactions between block copolymers and / or between the block copolymer and a hydrophobic drug. Alternatively, electrostatic interactions between the block copolymer and an anionic or cationic drug may occur when the poly(amino acid) has side chains containing cationic or anionic groups. Alternatively, drugs may be attached to the side chains of the second polymer segment.

[0050] The degree of polymerization of the second polymer segment may be, for example, 10-200, preferably 15-150, and more preferably 20-100.

[0051] The block copolymer to which the boronic acid group is attached can be, for example, a block copolymer represented by the formula: Z-L １ -Xa-L ２ -Xb (wherein Z represents a boronic acid group, Xa represents a first polymer segment, Xb represents a second polymer segment, and L １ and L ２ each independently represents a single bond or a linking group.

[0052] L １ and L ２The divalent linking group that may be represented by is not particularly limited as long as the effects of the present invention can be obtained. The linking group may be, for example, a linear or branched alkylene group having 1 to 6 carbon atoms, -COO-, -CONH-, -NH-, -CO-, -O-, -S-, or any combination thereof. The linking group may also contain a ring structure formed by click chemistry (e.g., a 1,2,3-triazole ring). The length of the linking group (the shortest number of atoms connecting the boronic acid group to which the linking group is bonded and the drug residue) may be, for example, 1 to 30, 1 to 20, or 1 to 10.

[0053] For specific examples of the block copolymer, reference can be made to WO2007 / 099660, WO2007 / 099661, WO2010 / 093036, WO2015 / 170757, and the like.

[0054] Various methods are known for forming the micelles and encapsulating drugs therein, and those skilled in the art can select any appropriate method.

[0055] A-2-2. Vesicles Vesicles can be closed sac-like aggregates formed by assembling a plurality of DDS carrier component molecules, including DDS carrier component molecules to which boronic acid groups are bound. The vesicles may encapsulate a drug inside. The drug may or may not be bound to the DDS carrier component molecules.

[0056] The number of boronic acid groups introduced per vesicle is not limited as long as the effects of the present invention are obtained, and can be appropriately selected depending on the size of the vesicle, etc. The number of boronic acid groups introduced is, for example, 1 to 10,000, and may be 5 or more or 10 or more, or 1,000 or less, 100 or less, or 20 or less. The boronic acid groups are preferably located on the outer surface of the vesicle. In other words, the vesicles preferably contain boronic acid groups exposed on their outer surface.

[0057] Vesicles include liposomes and polymersomes.

[0058] Liposomes may be vesicles formed, for example, by a two-layer molecular membrane. The two-layer molecular membrane may be formed by arranging amphipathic lipid molecules having a hydrophobic portion and a hydrophilic portion in a double layer with the hydrophobic portion facing inward. As shown in FIG. 2 , liposome 200 includes, as DDS carrier constituent molecules, amphipathic lipid molecules 210 a having a hydrophobic portion 212, a hydrophilic portion 214, and a boronic acid group 216 bound to the hydrophilic portion 214. If necessary, liposome 200 may further include amphipathic lipid molecules 210 b having a hydrophobic portion 212 and a hydrophilic portion 214 but no boronic acid group bound to the amphipathic lipid molecule. In the illustrated example, one boronic acid group is bound to each amphipathic lipid molecule, but two or more boronic acid groups may be bound to each amphipathic lipid molecule.

[0059] The amphipathic lipid molecule may be any biocompatible molecule, and a glycerophospholipid such as phosphatidylcholine may be preferably used. The boronic acid group may be bonded to the end of the hydrophilic portion of the amphipathic lipid molecule.

[0060] The liposome may be surface-modified with a biocompatible hydrophilic polymer. In this case, the hydrophilic polymer is introduced into the hydrophilic portion of the amphiphilic lipid molecule, and a boronic acid group may be introduced at the end of the hydrophilic polymer. Examples of biocompatible hydrophilic polymers include those described in Section A-1. Among these, poly(ethylene glycol) is preferred.

[0061] The amphiphilic lipid molecule having a boronic acid group attached thereto may have a structure represented by, for example, the formula: Z-Xc-Xd or Z-A-Xc-Xd (wherein Z represents the boronic acid group, Xc represents the hydrophilic portion, Xd represents the hydrophobic portion, and A represents the hydrophilic polymer segment).

[0062] The vesicles may be lipid nanoparticles. The lipid nanoparticles may have a structure in which ionized lipid molecules and a drug (e.g., nucleic acid) are encapsulated inside a lipid membrane containing so-called ionized lipid molecules, PEGylated lipid molecules, helper phospholipid molecules, and cholesterol. The lipid nanoparticles contain at least one lipid molecule having a boronic acid group bound thereto as a DDS carrier component. The boronic acid group may be bound, for example, to the PEG chain end of the PEGylated lipid molecule.

[0063] Examples of polymersomes include polymersomes composed of a cationic block copolymer having an uncharged hydrophilic polymer segment and a cationic polymer segment, and an anionic block copolymer or anionic homopolymer having an uncharged hydrophilic polymer segment and an anionic polymer segment, or polymersomes composed of the anionic block copolymer and the cationic block copolymer or cationic homopolymer. Such polymersomes can be formed by electrostatically complexing the cationic polymer segment or cationic homopolymer with the anionic polymer segment or anionic homopolymer, resulting in a spherical assembly with the uncharged hydrophilic polymer segment on the outside. Note that the cationic homopolymer refers to a polymer composed solely of cationic polymer segments, without both an uncharged hydrophilic polymer segment and a cationic polymer segment. Similarly, the anionic homopolymer refers to a polymer composed solely of anionic polymer segments, without both an uncharged hydrophilic polymer segment and an anionic polymer segment. Thus, each of these homopolymers may contain two or more types of structural units.

[0064] The uncharged hydrophilic polymer constituting the uncharged hydrophilic polymer segment may be poly(ethylene glycol). The cationic polymer or the cationic polymer constituting the cationic polymer segment may be a cationic poly(amino acid). The anionic polymer or the anionic polymer constituting the anionic polymer segment may be an anionic poly(amino acid). Specific examples of the polymersome and its constituent polymers may be found in WO 2012 / 014942, etc.

[0065] The polymersome may contain, as a DDS carrier component molecule, a cationic block copolymer having a boronic acid group bonded to the end of an uncharged hydrophilic polymer segment, and / or an anionic block copolymer having a boronic acid group bonded to the end of an uncharged hydrophilic polymer segment. By using such a cationic block copolymer and / or anionic block copolymer, a polymersome having boronic acid groups arranged on the surface can be obtained.

[0066] Various methods are known for forming the above-mentioned various vesicles and for encapsulating drugs therein, and those skilled in the art can select any appropriate method.

[0067] A-2-3. Polyion complex (PIC) Examples of PIC include PIC of a cationic polymer and an anionic drug, and PIC of an anionic polymer and a cationic drug. Examples of anionic drugs include nucleic acids and proteins. Examples of cationic drugs include proteins.

[0068] Examples of PICs of cationic polymers and anionic drugs include complexes (uPICs) consisting of structural units containing specific numbers of cationic block copolymers having hydrophilic and cationic polymer segments, and specific numbers of anionic drugs. For example, the uPIC contains one anionic drug and one or more cationic block copolymers. The uPIC may be, for example, a uPIC consisting of one molecule of cationic block copolymer and one molecule of anionic drug, a uPIC consisting of two molecules of cationic block copolymer and one molecule of anionic drug, or a uPIC consisting of three molecules of cationic block copolymer and one molecule of anionic drug. The boronic acid group may be bound to the cationic block copolymer or the anionic drug. In the former case, the boronic acid group may be bound to the hydrophilic polymer segment of the cationic block copolymer. In the latter case, the boronic acid group may be bound to the drug via the hydrophilic polymer. Alternatively, the boronic acid group may be attached to both the cationic block copolymer and the anionic drug, which may be a nucleic acid having a base length (base pair length in the case of a double-stranded nucleic acid) of 10 to 50 or 15 to 30.

[0069] The hydrophilic polymer segment of the cationic block copolymer typically contains a biocompatible hydrophilic polymer. The hydrophilic polymer may be a linear polymer, a branched polymer, or a graft polymer. Examples of such hydrophilic polymers include those described in Section A-1.

[0070] The molecular weight (Mw) of the hydrophilic polymer may be, for example, 1,000 to 100,000, preferably 10,000 to 50,000, and more preferably 20,000 to 40,000. When the hydrophilic polymer is a branched polymer (for example, a bibranched polymer) or a graft polymer, the molecular weight of the hydrophilic polymer may be the molecular weight of each branched chain or grafted chain.

[0071] The cationic polymer segment of the cationic block copolymer includes, for example, a cationic poly(amino acid). The cationic poly(amino acid) includes, for example, cationic amino acid residues having a cationic group (typically, an amino group) in the side chain. Examples of the cationic amino acid residue include basic amino acid residues such as lysine residue, ornithine residue, arginine residue, and histidine residue. Another example of the cationic amino acid residue is an aspartic acid residue or glutamic acid residue in which the -OH moiety of the carboxyl group (-C(O)OH) in the side chain is -NH-(CH ２ ) ｐ１ -[NH-(CH ２ ) ｑ１ - ｒ１ NH ２ (wherein p1 and q1 each independently represent an integer of 1 to 5, preferably 2 or 3, and more preferably 2; and r1 represents an integer of 1 to 5, preferably an integer of 1 to 3).

[0072] 3A is a schematic diagram illustrating an example of a uPIC composed of two molecules of a cationic block copolymer to which a boronic acid group is attached and one molecule of an anionic drug. uPIC 300A is composed of two molecules of a cationic block copolymer 310 and one molecule of an anionic drug (e.g., a nucleic acid) 320. Cationic block copolymer 310 has a hydrophilic polymer segment 312 and a cationic polymer segment 314, and has a boronic acid group 316 attached to the end of hydrophilic polymer segment 312. uPIC 300A is formed by electrostatic interaction between cationic polymer segment 314 of cationic block copolymer 310 and anionic drug 320.

[0073] For specific examples of the uPIC, reference can be made to WO2013 / 162041, WO2019 / 044937, etc.

[0074] In the illustrated example, the hydrophilic polymer segment 312 is composed of a linear polymer, but the hydrophilic polymer segment may also be composed of a branched polymer or a graft polymer. Examples of branched polymers and graft polymers include those described in Section A-1. In the illustrated example, one boronic acid group is bonded to each cationic block copolymer molecule, but two or more boronic acid groups may be bonded to each cationic block copolymer molecule. The boronic acid group may be bonded, for example, to the main chain or branched chain end, or the side chain or graft chain end of the hydrophilic polymer segment of the cationic block copolymer. Furthermore, unlike the illustrated example, uPIC may be composed of one or three or more molecules of cationic block copolymer 310 and one molecule of anionic drug 320. In this embodiment, it is sufficient that a boronic acid group is bonded to one or more of the cationic block copolymers constituting uPIC. Thus, for example, uPIC may be composed of a cationic block copolymer with boronic acid groups, a cationic block copolymer without boronic acid groups, and an anionic drug.

[0075] 3B is a schematic diagram illustrating an example of a uPIC composed of one molecule of a cationic block copolymer and one molecule of an anionic drug to which a boronic acid group is bound via a hydrophilic polymer. The cationic block copolymer 330 has a hydrophilic polymer segment 332 and a cationic polymer segment 334. The anionic drug 320 is bound to the boronic acid group 344 via the hydrophilic polymer segment 342. The uPIC 300B is formed by electrostatic interaction between the cationic polymer segment 334 of the cationic block copolymer 330 and the anionic drug 320. In this embodiment, the conjugate 340 of the anionic drug 320, the hydrophilic polymer segment 342, and the boronic acid group 344, and the cationic block copolymer 330, together function as DDS carrier constituent molecules.

[0076] In the illustrated example, the cationic block copolymer 330 does not have a boronic acid group, but a boronic acid group may be bonded to the cationic block copolymer 330 (preferably the hydrophilic polymer segment 332). Also, while the cationic block copolymer 330 contained in the uPIC 300B in the illustrated example is one molecule, it may contain two or more molecules. Furthermore, in the illustrated example, the hydrophilic polymer segments 332 and 342 are composed of linear polymers, but each of these hydrophilic polymer segments may be composed of a branched polymer or a graft polymer. Examples of branched polymers and graft polymers include those described in Section A-1. In the illustrated example, one boronic acid group is bonded per molecule of the conjugate, but two or more boronic acid groups may be bonded per molecule of the conjugate. The boronic acid group may be bonded, for example, to the main chain or branched chain end, or the side chain or graft chain end of the hydrophilic polymer segment of the conjugate.

[0077] Other examples of PICs include PICs of cationic poly(amino acids) and anionic drugs, or PICs of anionic poly(amino acids) and cationic drugs. The cationic poly(amino acids) contain cationic amino acid residues with cationic groups in their side chains. The anionic poly(amino acids) contain anionic amino acid residues with anionic groups in their side chains. The PICs can be composed of an unspecified number of poly(amino acids) and an unspecified number of drug molecules. Such PICs contain poly(amino acids) with boronic acid groups as DDS carrier constituent molecules, and may further contain poly(amino acids) without boronic acid groups, depending on the purpose. The boronic acid group can be bound, for example, to at least one end of the poly(amino acids). If necessary, any appropriate linker or hydrophilic polymer segment may be interposed between the poly(amino acids) and the boronic acid group.

[0078] A-3. Drug delivery particles containing a drug having a boronic acid group bonded thereto Drug delivery particles containing a drug having a boronic acid group bonded thereto may be composed of the above-mentioned drug having a boronic acid group bonded thereto. The number of drugs contained in the drug delivery particles containing a drug having a boronic acid group bonded thereto may be one.

[0079] Examples of the drug include those described in section A-1.

[0080] The number of boronic acid groups bonded per drug molecule is not limited as long as the effects of the present invention are obtained, and can be appropriately selected depending on the chemical structure, steric structure, molecular weight, etc. The number of boronic acid groups bonded is, for example, 1 to 200, and may be 3 or more or 5 or more, or 100 or less, 50 or less, or 10 or less.

[0081] The boronic acid group may be directly bound to the drug or may be bound via a linker, and in one embodiment, the boronic acid group is bound to one drug via two or more linkers.

[0082] The linker is not particularly limited, and examples thereof include the linkers described in Section A-2. Furthermore, for example, a biocompatible polymer can be used as the linker. The biocompatible polymer is preferably a hydrophilic polymer. Furthermore, the biocompatible polymer may be a linear polymer, a branched polymer, or a graft polymer. Examples of biocompatible hydrophilic polymers include those described in Section A-1. The boronic acid group can be bonded, for example, to the main chain or branched chain end, or the side chain or graft chain end of the polymer. A specific example of an embodiment using a branched polymer as a linker is an embodiment in which a drug is bonded to the central portion of a dendron having a boronic acid group introduced into one or more of its terminal groups. In this embodiment, the number of dendrons bonded to a drug may be two or more.

[0083] B. Pharmaceutical Compositions Pharmaceutical compositions according to embodiments of the present invention contain the drug delivery particles described in Section A and may further contain any appropriate additives depending on the intended purpose. The type and amount of additives can be appropriately determined by those skilled in the art depending on the intended purpose. Specific examples of additives include excipients, isotonicity agents, pH adjusters, buffers, stabilizers, etc.

[0084] In one embodiment, the pharmaceutical composition is an injectable preparation. The injectable pharmaceutical composition may be a powder formulation, a lyophilized formulation, or a liquid formulation. The liquid formulation, for example, contains an aqueous medium, optionally buffered. When the drug delivery particles are micelles, vesicles, or PICs, the micelles, vesicles, or PICs may be formed in the aqueous medium. On the other hand, powder formulations and lyophilized formulations are dissolved or dispersed in an aqueous medium, such as water for injection, before use. When the drug delivery particles are micelles, vesicles, or PICs, the micelles, vesicles, or PICs may be formed in the solution or dispersion.

[0085] The disease to be treated by the pharmaceutical composition can be a disease that requires delivery of a drug to the heart and / or diaphragm.Such diseases include Duchenne muscular dystrophy, heart failure, myocardial infarction, dilated cardiomyopathy, cardiac hypertrophy, etc.For example, in Duchenne muscular dystrophy, treatment using antisense nucleic acid has been considered.

[0086] The pharmaceutical composition may be administered via intravenous administration, intracoronary administration, intramyocardial administration, etc. The subject of administration is typically a human or a non-human mammal (such as a mouse, rat, rabbit, monkey, dog, or horse).

[0087] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples in any way.

[0088] Experimental Example 1: Drug delivery particles containing 8-branched poly(ethylene glycol) as a DDS carrier constituent molecule 1. Raw materials: Amine-terminated 8-branched polyethylene glycol (8arm-PEG), molecular weight 20,000 (purchased from SINOPEG, used as is, product name: 8arm PEG-NH2(TP)) N,N-dimethylformamide (DMF) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Dichloromethane (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Acetic anhydride (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Methanol (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Succinic anhydride (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Triethylamine (TEA) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Sodium bicarbonate (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) 4-Carboxy-3-fluorophenylboronic acid (FPBA) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) p-Carboxyphenylboronic acid (PBA) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) m-Aminophenylboronic acid (APBA) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Benzoyl chloride (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) D-PBS(-) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Sulfo-Cy5-NHS (purchased from Lumiprobe, dissolved in DMSO at a concentration of 25 mg / mL and used as is) 6-carboxypyridine-3-boronic acid (PyBA) (purchased from Combi-Block, used as is)

[0089] 500 mg of 8arm-PEG was dissolved in 10 mL of DMF, and 15.5 mg of sulfo-Cy5-NHS (622 μL) was added. The mixture was stirred overnight and reacted. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500 and dialyzed for two days, after which the mixture was recovered by lyophilization.

[0090] 2-2. Synthesis of Cy5-8arm-PyBA (Introduction of PyBA) PyBA (17 mg) and sodium bicarbonate (8 mg) were added to Cy5-8arm-PEG (50 mg), and 2 mL of DMF was added and stirred. DMT-MM (30 mg) was then added and reacted overnight. The reaction solution was filtered through a 0.45 μm filter. The filtrate was placed in a dialysis membrane with a molecular weight cutoff of 3500 and dialyzed for two days, after which it was recovered by lyophilization.

[0091] 2-3. Synthesis of Cy5-8arm-FPBA (Introduction of FPBA) FPBA (19 mg) was added to Cy5-8arm-PEG (50 mg) and dissolved in 2 mL of methanol. DMT-MM (30 mg) was then added and reacted overnight. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500 and dialyzed for two days, after which the product was recovered by lyophilization.

[0092] 2-4. Synthesis of Cy5-8arm-PBA (incorporation of PBA) PBA (17 mg) was added to Cy5-8arm-PEG (50 mg) and dissolved in 2 mL of methanol. DMT-MM (30 mg) was then added and reacted overnight. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500 and dialyzed for two days, after which the product was recovered by lyophilization.

[0093] 2-5. Synthesis of Cy5-8arm-APBA (Introduction of APBA) Cy5-8arm-PEG (50 mg) was dissolved in 2 mL of dichloromethane, and TEA (6 μL) and succinic anhydride (4 mg) were added and reacted overnight. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500, dialyzed for two days, and then recovered by lyophilization. The recovered Cy5-8arm-PEG-succinic acid was then dissolved in 2 mL of methanol, and APBA (14 mg), DMT-MM (30 mg), and sodium bicarbonate (4 mg) were added and reacted overnight. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500, dialyzed for two days, and then recovered by lyophilization.

[0094] 2-6. Synthesis of Cy5-8arm-Phenyl (Introduction of Phenyl) Cy5-8arm-PEG (50 mg) was dissolved in 2 mL of dichloromethane, and TEA (14 μL) and benzoyl chloride (12 μL) were added and reacted overnight. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500 and dialyzed for 2 days, after which the solution was recovered by lyophilization.

[0095] 2-7. Synthesis of Cy5-8arm-Ace (Introduction of Ace) Cy5-8arm-PEG (50 mg) was dissolved in 2 mL of dichloromethane, and TEA (14 μL) and acetic anhydride (10 μL) were added and reacted overnight. The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 3500 and dialyzed for 2 days, after which the product was recovered by lyophilization.

[0096] In this manner, hyperbranched polymers (Cy5-8arm-PyBA, Cy5-8arm-FPBA, Cy5-8arm-PBA, Cy5-8arm-APBA, Cy5-8arm-Phenyl, Cy5-8arm-Ace) were obtained, each having a structure in which Cy5 was bound to one of the residues shown below the eight terminal amino groups of 8arm-PEG shown below. Note that the -NH- of the amide bond at the binding site of each residue is derived from the terminal amino group of 8arm-PEG.

[0097] The hyperbranched polymers obtained in 2-2 to 2-7 above were subjected to NMR analysis under the following conditions. As a result, the average number of Cy5 bonds per polymer molecule was 0.9, and the average number of each ligand was 6.5 or more. Furthermore, the hyperbranched polymers obtained in 2-2 to 2-6 above were subjected to FCS analysis under the following conditions. As a result, the particle diameter of each hyperbranched polymer was in the range of 8 nm to 10 nm. <NMR Analysis> The hyperbranched polymers were subjected to D ２The measurement sample was obtained by dissolving the polymer in D-PBS(-) at a concentration of 10 mg / mL. The measurement sample was subjected to NMR measurement using a JEOL NMR spectrometer (ECS-400) to calculate the number of introduced ligands. The measurement conditions were set at 25°C and an accumulation of 64 times. <FCS analysis> The hydrodynamic diameter of the hyperbranched polymer was measured using an Olympus FCS spectrometer (MF20). The hyperbranched polymer was dissolved in D-PBS(-) at a concentration of 5 mg / L. Cy5 dye, as a standard dye, was dissolved in D-PBS(-) at a concentration of 10 nM, and the diffusion times of the hyperbranched polymer and Cy5 dye were measured. The hydrodynamic diameter was calculated based on the obtained diffusion times.

[0098] 3. Pharmacokinetic Evaluation The above hyperbranched polymer was dissolved in D-PBS(-) to a concentration of 10 μM, and 200 μL of this solution was administered to mice (C57 / BL6, female, 7 weeks old) via the tail vein. 24 hours after administration, the mice were dissected, and the accumulation rate of the hyperbranched polymer in each organ was calculated from the Cy5 fluorescence intensity in the blood and in the homogenate of the collected organs (tissues). The results are shown in Figure 4 (in the figure, the bars indicate the average value of n = 3, and the error bars indicate the standard deviation).

[0099] As shown in Figure 4, Cy5-8arm-PyBA, Cy5-8arm-FPBA, Cy5-8arm-PBA, and Cy5-8arm-APBA, into which a boronic acid group was introduced, all showed higher accumulation in the heart than Cy5-8arm-Ace, which had no ligand. Among these, Cy5-8arm-PyBA, Cy5-8arm-FPBA, and Cy5-8arm-PBA showed a remarkable effect in increasing accumulation. On the other hand, Cy5-8arm-Phenyl, into which a phenyl group was introduced, did not show an effect in increasing accumulation in the heart. Furthermore, Cy5-8arm-PyBA, Cy5-8arm-FPBA, and Cy5-8arm-PBA also showed a remarkable effect in increasing accumulation in the diaphragm.

[0100] Experimental Example 2: Drug delivery particles containing graft polymer as a DDS carrier constituent molecule 1. Raw materials: Azide-PEG3-amine (purchased from Tokyo Chemical Industry Co., Ltd., used as is) N,N-dimethylformamide (DMF) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is or after distillation with calcium hydride) Dimethyl sulfoxide (DMSO) (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) Dichloromethane (purchased from Fujifilm Wako Pure Chemical Industries, Ltd., used as is) β-benzyl-L-aspartic acid N-carboxylic anhydride (NCA-BLA) (purchased from Chuo Kaseihin Co., Ltd., used as is) Product name: "SUNBRIGHT MEPA-20H" (methoxy-PEG-amine with an average molecular weight of 2,000, purchased from NOF Corporation, used as is) Product name: "SUNBRIGHT BO-020EA" (Boc-protected amine-PEG-amine with an average molecular weight of 2,000, purchased from NOF Corporation, used as is) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (purchased from Fujifilm Wako Pure Chemical Industries, used as is) N-Hydroxysuccinimide (purchased from Fujifilm Wako Pure Chemical Industries, used as is) Diethyl ether (purchased from Fujifilm Wako Pure Chemical Industries, used as is) Acetonitrile (purchased from Fujifilm Wako Pure Chemical Industries, used as is) Sodium hydroxide (purchased from Fujifilm Wako Pure Chemical Industries, used as is) Sodium bicarbonate (purchased from Fujifilm Wako Pure Chemical Industries, used as is) Trifluoroacetic acid (purchased from Fujifilm Wako Pure Chemical Industries, used as is) Sulfo-Cy5-DBCO (purchased from Lumiprobe, used as is) D-PBS (-) (purchased from Fujifilm Wako Pure Chemical Industries, used as is)

[0101] 2-1. Synthesis of PBLA and Polyaspartic Acid (PAsp) 1,000 mg of NCA-BLA was weighed into a round-bottom flask and dissolved in 2 mL of DMF. In a separate round-bottom flask, 724 μL of azide-PEG3-amine solution diluted 100-fold with dichloromethane and 18 mL of dichloromethane were added and mixed. The entire NCA-BLA solution was added to the azide-PEG3-amine solution and stirred for 3 days at 35°C. All of the above reactions were carried out under an argon atmosphere, and all organic solvents used were distilled prior to use. After the reaction, the reaction solution was added dropwise to 400 mL of diethyl ether to precipitate PBLA. The precipitate was then collected by suction filtration and dried under reduced pressure. The degree of polymerization of the resulting PBLA was measured by NMR, and the degree of polymerization was calculated to be 101. After suspending 100 mg of PBLA in 1 mL of acetonitrile, 4.9 mL of 0.5 M aqueous sodium hydroxide solution was added and stirred overnight at room temperature. The reaction solution was then placed in a dialysis membrane (molecular weight cutoff: 6,000-8,000) and dialyzed twice with pure water as the external solution, twice with 0.01 M hydrochloric acid, and twice again with pure water (for at least 2 hours each), followed by lyophilization to obtain polyaspartic acid (PAsp). All dialysis was performed in a refrigerator.

[0102] 2-2. Synthesis of PyBA-PEG-amine DMF (5 mL) was added to BO-020EA (250 mg), PyBA (104 mg), and sodium bicarbonate (20 mg). After thorough stirring, DMT-MM (180 mg) was added and the mixture was allowed to react overnight. Insoluble matter was removed from the reaction mixture using a 0.45 μm filter, and the mixture was added dropwise to 100 mL of diethyl ether and dried to obtain a white powder. Dichloromethane (2.5 mL) and trifluoroacetic acid (250 μL) were added, and the mixture was allowed to react at room temperature overnight. The insoluble matter was removed using a 0.45 μm filter, and the mixture was added dropwise to 50 mL of diethyl ether and dried to obtain a white powder (PyBA-PEG-amine).

[0103] 2-3. Synthesis of FPBA-PEG-amine Methanol (5 mL) was added to BO-020EA (250 mg) and FPBA (115 mg), and after thorough stirring, DMT-MM (180 mg) was added and the mixture was allowed to react overnight. Insoluble matter was removed from the reaction solution using a 0.45 μm filter, and after drying under reduced pressure, the mixture was redissolved in dichloromethane (5 mL). After removing insoluble matter using a 0.45 μm filter, the mixture was added dropwise to 100 mL of diethyl ether and dried to obtain a white powder. Dichloromethane (2.5 mL) and trifluoroacetic acid (250 μL) were added, and the mixture was allowed to react at room temperature overnight. Insoluble matter was removed using a 0.45 μm filter, and the mixture was added dropwise to 50 mL of diethyl ether and dried to obtain a white powder (FPBA-PEG-amine).

[0104] 2-4. Introduction of Various PEGs (MEPA-20H, PyBA-PEG-amine, FPBA-PEG-amine) into PAsp Introduction of MEPA-20H: PAsp (3 mg) was weighed and dissolved in 1.5 mL of a 50% mixed solvent of DMF and DMSO. 150 mg of MEPA-20H was weighed into a separate sample bottle and dissolved in DMF (3 mL). N-hydroxysuccinimide (14.65 mg) and EDC (4 mg) were added to the PAsp solution and stirred at room temperature for 30 minutes, after which 2.36 mL of PEG solution was added and the mixture was allowed to react overnight. PyBA-PEG-amine and FPBA-PEG-amine were also introduced in a similar manner.

[0105] The reaction solution was placed in a dialysis membrane with a molecular weight cutoff of 12,000-14,000 and dialyzed twice against PBS, then purified by ultrafiltration (molecular weight cutoff 30,000) and recovered by freeze-drying.

[0106] The number of PEG molecules introduced into PAsp was calculated by measuring the decrease in the peak area of ​​each PEG from its initial value using GPC. From the GPC results, the average number of PEG molecules introduced was calculated to be 52 for MEPA-20H, 50 for PyBA-PEG-amine, and 57 for FPBA-PEG-amine.

[0107] 2-5. Fluorescent labeling of each graft polymer (incorporation of Cy5) Graft polymers (15 mg) incorporating various PEG groups were dissolved in pure water, and 7 μL of a Sulfo-Cy5-DBCO solution adjusted to a concentration of 25 mg / mL with DMSO was added. After stirring, the mixture was left to stand overnight at -20°C and then redissolved in a refrigerator. The resulting solution was placed in a dialysis membrane with a molecular weight cutoff of 12,000-14,000 and dialyzed four times against pure water, after which the mixture was recovered by lyophilization.

[0108] In this manner, the following three types of graft polymers (polyPyBA, polyFPBA, and polyPEG) were obtained (where L represents a divalent linker, m is 101, and R １ The number of introduced amino acid residues is 50 for PyBA-PEG, 57 for FPBA-PEG, and 52 for PEG, and each amino acid residue is present randomly).

[0109] DLS analysis was performed under the following conditions for each of the graft polymers obtained in 2-5 above. As a result, the particle size of each graft polymer was within the range of 12 nm to 20 nm. <DLS analysis> The hydrodynamic diameter of the graft polymer was measured using a DLS device (Mobius) manufactured by Wyatt Technology. The graft polymer was dissolved in D-PBS(-) at a concentration of 5 mg / mL, and the hydrodynamic diameter was measured.

[0110] 3. Pharmacokinetic Evaluation The above graft polymer was dissolved in D-PBS(-) to a concentration of 10 μM, and 200 μL of this solution was administered to mice (C57 / BL6, female, 7 weeks old) via the tail vein. 48 hours after administration, the mice were dissected, and the accumulation rate of the graft polymer in each organ was calculated from the Cy5 fluorescence intensity in the blood and in the homogenate of the collected organs (tissues). The results are shown in Figures 5A and 5B (in the figures, the bars indicate the average value (n = 3), and the error bars indicate the standard deviation). Note that Figure 5B shows the relative accumulation amount when the accumulation amount of polyPEG is set to 1.

[0111] As shown in Figures 5A and 5B, both polyPyBA and polyFPBA grafted with PEG containing boronic acid groups showed higher accumulation in the heart and diaphragm than polyPEG grafted with PEG not containing boronic acid groups.

[0112] The drug delivery particles of the present invention can be suitably used in the delivery of drugs targeted to the heart and / or diaphragm in the medical field.

Claims

1. Particles for drug delivery to the heart and / or diaphragm having boronic acid groups as targeting moieties.

2. The drug delivery particle according to claim 1, wherein the boronic acid group is in the form of a phenylboronic acid group or a pyridineboronic acid group.

3. The drug delivery particles according to claim 1, having a particle diameter of 100 nm or less.

4. The drug delivery particle according to claim 1, comprising a drug transporter component molecule to which the boronic acid group and a drug are bound.

5. The drug delivery particle according to claim 4, wherein the drug transporter component molecule is a linear polymer, a branched polymer, or a graft polymer.

6. The drug delivery particle according to claim 1, which contains a specific number of drug transporter component molecules and drug complexes, and the boronic acid group is bound to at least one of the drug transporter component molecules and the drug.

7. The drug delivery particle of claim 1, comprising a micelle or vesicle containing a drug transporter component molecule to which the boronic acid group is bound.

8. The drug delivery particle according to claim 7, further comprising a drug, wherein the drug is encapsulated in the micelle or the vesicle.

9. The drug delivery particle of claim 1, comprising a drug having the boronic acid group attached thereto.

10. The drug delivery particle according to claim 1, which is used to treat a disease requiring delivery of a drug to the heart and / or diaphragm.

11. A pharmaceutical composition comprising the drug delivery particles of claim 1.

12. Use of boronic acid groups to target drugs or drug transporters to the heart and / or diaphragm.

13. Use of a boronic acid compound for producing the drug delivery particles described in claim 1.

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