Hyaluronic acid derivative pharmaceutical composition

Abstract

To provide a hyaluronic acid-derived pharmaceutical composition excellent in water solubility of a hardly water-soluble drug, especially a compound having a site targeting E3 ligase such as PROTAC molecules.SOLUTION: A hyaluronan derivative pharmaceutical composition comprising (A) a hyaluronan derivative into which a steryl group is introduced, and (B) an active ingredient, wherein the (B) active ingredient is a compound having a site that targets E3 ligase and a divalent group having a molecular weight of 70 or more and 300 or less, and the hyaluronan derivative pharmaceutical composition, wherein the divalent group has 1 or more and 5 or less oxyalkylene groups having 1 to 6 carbon atoms.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for administering a poorly water-soluble drug using a hyaluronic acid derivative as a carrier. [Background technology]

[0002] In recent years, biopharmaceuticals, which are pharmaceuticals that use proteins, peptides, or nucleic acids as active ingredients, have been put into practical use, and their number is increasing year by year. Biopharmaceuticals can fulfill unmet medical needs that could not be met by conventional small molecule drugs.

[0003] In particular, drug development utilizing targeted protein degradation (TPD) has been active, which achieves the desired therapeutic effect by utilizing the in vivo ubiquitin-proteasome system (UPS) to degrade pathogenic proteins. TPD utilizes proteolysis-targeting chimeric protein compounds (PROTAC molecules), which link a ligand for E3 ligase (EC:2.3.2.27) with a molecule that binds to a target protein degraded by the UPS (Non-Patent Document 1). E3 ligases recruit E2 ubiquitin-conjugating enzymes, recognize target proteins, and transfer ubiquitin from the E2 enzyme to the target protein. It is estimated that there are approximately 500 to 1,000 types of E3 ligases in humans, and numerous E3 ligases and their ligands have been reported (Non-Patent Document 2).

[0004] However, many PROTAC molecules are polymeric and poorly water-soluble, which means that even when formulated, their bioavailability is often insufficient. Therefore, methods to improve the solubility of PROTAC molecules are needed to enhance their bioavailability.

[0005] A method using hyaluronic acid derivatives as carriers to improve the solubility of poorly water-soluble drugs is known. Hyaluronic acid derivatives spontaneously associate in aqueous solution, enabling poorly water-soluble drugs to be efficiently encapsulated while retaining their biological activity (Patent Document 1).

[0006] When hyaluronic acid derivatives are used as carriers, methods for further improving bioavailability have also been developed. For example, it is known that hyaluronic acid derivatives modified with cationic groups and polyethylene glycol and further having hydrophobic groups introduced therein have excellent adhesiveness to mucous membranes and mucosal permeability (Patent Document 2). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2010 / 053140 [Patent Document 2] International Publication No. 2019 / 098393 [Non-patent literature]

[0008] [Non-Patent Document 1] Liu et al., Molecular Biomedicine, 2022, vol.3, article no.46. [Non-patent document 2] Cell Signaling Technology, "Ubiquitin Ligase Table," [online], searched June 7, 2024, Internet <URL:https: / / www.cellsignal.jp / learn-and-support / reference-tables / ubiquitin-ligase-table> Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention aims to provide a hyaluronic acid derivative pharmaceutical composition that exhibits excellent water solubility for poorly water-soluble drugs, particularly compounds having a site that targets E3 ligase, such as a PROTAC molecule. [Means for solving the problem]

[0010] That is, the present invention includes the following aspects. [1] (A) a hyaluronic acid derivative having a steryl group introduced therein; and (B) an active ingredient, A hyaluronic acid derivative pharmaceutical composition, wherein the active ingredient (B) is a compound having a site that targets E3 ligase and a divalent group having a molecular weight of 70 or more and 300 or less. [2] The pharmaceutical composition of a hyaluronic acid derivative according to [1] above, wherein the divalent group has an oxyalkylene group having 1 to 6 carbon atoms and 1 to 5 carbon atoms. [3] The pharmaceutical composition of the hyaluronic acid derivative according to [1], wherein the divalent group has a group in which two groups selected from the group consisting of aliphatic cyclic groups and aliphatic heterocyclic groups, or one group selected from the group consisting of aliphatic cyclic groups and aliphatic heterocyclic groups and one group selected from the group consisting of aryl groups and heteroaryl groups, are linked by an alkylene group having 1 to 6 carbon atoms. [4] The active ingredient (B) is a compound having a site that targets the E3 ligase and a site that binds to a target protein to be degraded by the E3 ligase, The hyaluronic acid derivative pharmaceutical composition of any one of [1] to [3] above, wherein the divalent group links the site that targets the E3 ligase with the site that binds to the target protein to be degraded by the E3 ligase, or the site that binds to the target protein to be degraded by the E3 ligase contains the divalent group. [5] The hyaluronic acid derivative pharmaceutical composition according to any one of [1] to [4] above, wherein the active ingredient (B) is a proteolysis-inducing chimeric protein compound. [6] The hyaluronic acid derivative pharmaceutical composition according to any one of [1] to [5] above, wherein the site that targets E3 ligase is a VHL ligand or a CRBN ligand. [7] The hyaluronic acid derivative pharmaceutical composition according to any one of [4] to [6], wherein the target protein is a protein selected from the group consisting of an androgen receptor, an estrogen receptor, a BET family protein, an IKAROS transcription factor family protein, and a Bcl family protein. [8] The hyaluronic acid derivative pharmaceutical composition according to any one of [5] to [7] above, wherein the molecular weight of the proteolysis-inducing chimeric protein compound is 500 or more and 5,000 or less. [9] The hyaluronic acid derivative pharmaceutical composition according to any one of [5] to [8] above, wherein the solubility of the proteolysis-inducing chimeric protein compound in water is 1 mg / mL or less.

[10] The hyaluronic acid derivative pharmaceutical composition according to any one of [5] to [9], wherein the proteolysis-inducing chimeric protein compound is ARV-110, ARV-825, CC220, MZ-1, or ARCC-4.

[11] The pharmaceutical composition of any one of [1] to

[10] above, wherein the average molecular weight of the hyaluronic acid derivative (A) into which a steryl group has been introduced is 3,000 or more and 40,000 or less.

[12] The pharmaceutical composition of any one of [1] to

[11] above, wherein the steryl group introduction rate of the hyaluronic acid derivative (A) into which a steryl group has been introduced is 15 to 60%.

[13] The pharmaceutical composition of any one of [1] to

[12] above, wherein the (A) hyaluronic acid derivative having a steryl group introduced therein has one or more repeating units represented by the following general formula (I):

[0011] [ka]

[0012] (In the formula, R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, formyl and C 1-6 alkylcarbonyl. Z represents a direct bond or a peptide linker consisting of any amino acid residues of 2 to 30. X 1 is -NR b -R, -NR b -COO-R, -NR b -CO-R, -NRb -CO-NR c -R, -COO-R, -O-COO-R, -SR, -CO-Y a -SR, -O-CO-Y b -SR, -NR b -CO-Y b It is a group selected from the group consisting of groups represented by -SR and -SSR. R a , R b and R c are each independently a hydrogen atom, C 1-20 Alkyl, Amino C 2-20 Alkyl and Hydroxy C 2-20 R is a group selected from the group consisting of alkyl. a , R b and R c The alkyl portion of is -O- and -NR f A group selected from the group consisting of - may be inserted. R f is a hydrogen atom, C 1-12 Alkyl, Amino C 2-12 Alkyl and Hydroxy C 2-12 R is a group selected from the group consisting of alkyl. f The alkyl portion of the formula (I) may be inserted with a group selected from the group consisting of -O- and -NH-. R is a steryl group. Y is C 2-30 Alkylene, or -(CH2CH2O) m -CH2CH2-. Here, the alkylene of Y is -O-, -NR g A group selected from the group consisting of - and -SS- may be inserted. R g is a hydrogen atom, C 1-20 Alkyl, Amino C 2-20 Alkyl and Hydroxy C 2-20 R is a group selected from the group consisting of alkyl. g The alkyl portion of the formula (I) may be inserted with a group selected from the group consisting of -O- and -NH-. Y a is C 1-5 It is alkylene. Y b is C 2-8 Alkylene or C 2-8 It is alkenylene. m is an integer between 1 and 100.

[14] The pharmaceutical composition of a hyaluronic acid derivative according to any one of [1] to

[13] above, wherein the steryl group is a cholesteryl group.

[15] A method for improving the water solubility of a poorly water-soluble drug, comprising: A method for complexing the poorly water-soluble drug with a hyaluronic acid derivative having a steryl group introduced therein, the poorly water-soluble drug being introduced with a structure having an oxyalkylene group with a molecular weight of 70 or more and 300 or less and 1 to 5 carbon atoms.

[16] The method of

[15] , wherein the oxyalkylene group-containing poorly water-soluble drug is a compound in which a first poorly water-soluble drug and a second poorly water-soluble drug are linked by a structure having the oxyalkylene group. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a hyaluronic acid derivative pharmaceutical composition that contains a poorly water-soluble drug, in particular a compound having a site that targets E3 ligase, such as a PROTAC molecule, as an active ingredient, and that has excellent water solubility. DETAILED DESCRIPTION OF THE INVENTION

[0014] The following describes in detail an embodiment of the present invention (hereinafter referred to as "the present embodiment"); however, the present invention is not limited to this embodiment, and various modifications are possible without departing from the spirit of the present invention.

[0015] The terms used in this specification will be explained below.

[0016] As used herein, "C 1-20The term "alkyl" means a straight or branched chain alkyl group having from 1 to 20 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, etc. 1-4 alkyl," and further includes n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, and the like. 1-20 Alkyl has 1 to 12 carbon atoms. 1-12 Alkyl, carbon number 1 to 6, C 1-6 Alkyl groups are also included.

[0017] As used herein, "C 1-6 The term "alkylcarbonyl" refers to the alkyl moiety of the already mentioned C 1-6 It means an alkylcarbonyl group, for example, acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, etc. 1-4 alkylcarbonyl".

[0018] As used herein, "amino acid C" 2-20 The term "alkyl" means a linear or branched alkyl having from 2 to 20 carbon atoms and having an amino group as a substituent, for example, the amino group may be located on the terminal carbon atom of the alkyl group. 2-20 Alkyl includes amino C with 2 to 12 carbon atoms. 2-12 Alkyl is also included.

[0019] As used herein, "hydroxy C 2-20 The term "alkyl" means a linear or branched alkyl group having from 2 to 20 carbon atoms and having a hydroxy group as a substituent, for example, the hydroxy group may be located on the terminal carbon atom of the alkyl group.2-20 Alkyl has 2 to 12 carbon atoms and hydroxy C 2-12 Alkyl is also included.

[0020] As used herein, "C 2-30 The term "alkylene" means a linear or branched divalent saturated hydrocarbon group having from 2 to 30 carbon atoms, and includes, for example, ethylene, propylene, etc., and has from 2 to 20 carbon atoms. 2-20 Alkylene, C with 2 to 8 carbon atoms 2-8 Alkylene, group -(CH2) n -" (where n is 2 or more and 30 or less, preferably 2 or more and 20 or less, and more preferably 2 or more and 15 or less).

[0021] As used herein, "C 1-5 The term "alkylene" means a linear or branched divalent saturated hydrocarbon group having from 1 to 5 carbon atoms, and includes, for example, methylene, ethylene, propylene, butylene, pentylene, etc. 1-6 The term "alkylene" means a straight or branched chain saturated divalent hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0022] As used herein, "C 2-8 The term "alkenylene" means a linear or branched, divalent saturated hydrocarbon group containing from 2 to 8 carbon atoms and containing one or more double bonds, and includes, for example, -CH=CH-, -C(CH3)=CH-, 2-butene-1,4-diyl, hepta-2,4-diene-1,6-diyl, octa-2,4,6-triene-1,8-diyl, etc. When geometric isomers exist, each isomer and a mixture thereof are also included.

[0023] In the present invention and the present specification, the term "solubility" means solubility in water, unless otherwise specified.

[0024] <Hyaluronic acid derivative pharmaceutical composition> The hyaluronic acid derivative pharmaceutical composition of this embodiment is a hyaluronic acid derivative pharmaceutical composition, which comprises (A) hyaluronic acid derivative with steryl group introduced therein, and (B) active ingredient, and said (B) active ingredient is a compound having a site that targets E3 ligase and a divalent group with molecular weight of 70 or more and 300 or less. Hereinafter, "hyaluronic acid derivative pharmaceutical composition" may be abbreviated as "pharmaceutical composition".

[0025] In the pharmaceutical composition of this embodiment, the hyaluronic acid derivative forms a complex with the active ingredient (hereinafter, sometimes referred to as an "active ingredient-hyaluronic acid derivative complex"). Specifically, the steryl group in the hyaluronic acid derivative and the hydrophobic portion of the active ingredient form a complex through hydrophobic interaction. The form of the complex is not particularly limited and is appropriately determined depending on the size of the hyaluronic acid derivative, the type and size of the active ingredient, the content ratio of the hyaluronic acid derivative to the active ingredient, etc. For example, the complex may have a cylindrical structure in which the active ingredient and the hydrophobic portion, such as the steryl group, are present in the center and the hydrophilic portion, such as the portion derived from hyaluronic acid in the hyaluronic acid derivative, is present in the outer periphery, i.e., the active ingredient is encapsulated or encapsulated in the hyaluronic acid derivative. Alternatively, the hyaluronic acid derivative and the active ingredient may be entangled with each other, and the active ingredient may be amorphous (non-crystalline structure).

[0026] In the pharmaceutical composition of this embodiment, the average particle size of the structure containing the active ingredient-hyaluronic acid derivative complex is not particularly limited, but can be 10nm or more, preferably 20nm or more, more preferably 30nm or more.In the pharmaceutical composition of this embodiment, the average particle size of the structure can be 500nm or less, preferably 400nm or less, more preferably 300nm or less, even more preferably 220nm or less, can be 150nm or less, can be 100nm or less.By having the average particle size within the above numerical range, sterilization filtration is possible, and the active ingredient-hyaluronic acid derivative complex can be stably present in the living body, and the effect of the hyaluronic acid derivative as a drug carrier can be more strongly exhibited.

[0027] The average particle size of the structure containing the active ingredient-hyaluronic acid derivative complex can be measured by, for example, DLS (Dynamic Light Scattering), nanotracking particle measuring device, size exclusion chromatography, high performance liquid chromatography, electron microscope, etc. More specifically, for example, the hyaluronic acid derivative is diluted with 10 mM phosphate buffer containing 10 w / v% sucrose in a proportion that the concentration of the hyaluronic acid derivative becomes 1 mg / mL, and measured by a DLS device, and the 50% integrated value of the obtained particle size distribution (integral distribution curve) is calculated as the average particle size.

[0028] Next, the components of this embodiment will be described in detail below.

[0029] <Hyaluronic acid derivatives with steryl groups> The pharmaceutical composition of this embodiment comprises (A) a hyaluronic acid derivative into which a steryl group has been introduced, and the average molecular weight of the (A) hyaluronic acid derivative is 3,000 or more and 40,000 or less. Hereinafter, "(A) a hyaluronic acid derivative into which a steryl group has been introduced" may be referred to as "(A) hyaluronic acid derivative".

[0030] The steryl group may be directly bound to hyaluronic acid or may be bound via a linker. The "linker" referred to here is a group in which a group reactive with a carboxy group and a group reactive with a steryl group are linked by a chain group (spacer). Examples of the group reactive with a carboxy group and the group reactive with a steryl group include an amino group and a hydroxyl group. Examples of the chain group include a chain hydrocarbon group, a polyethylene glycol (PEG) chain, any peptide linker that can be introduced by genetic engineering, or a synthetic compound linker. The length of the linker is not particularly limited and can be appropriately selected by those skilled in the art depending on the purpose. Examples of the chain hydrocarbon group include C 1-30 Alkylene is preferred, C 1-10 Alkylene is more preferred, C 1-6Alkylene is more preferred. As the PEG group, a group in which the number of linked ethylene glycol groups is 1 to 15 is preferred, a group in which the number is 1 to 10 is more preferred, and a group in which the number is 1 to 5 is even more preferred. As the peptide linker, two or more amino acids (the upper limit is not particularly limited, but usually 30 or less amino acids, preferably 20 or less amino acids) are used, and 15 amino acids are particularly preferred. As the hyaluronic acid derivative of this embodiment, it is preferred that at least a portion of the carboxyl groups in the glucuronic acid moiety are linked to steryl groups via a linker having a chain-like hydrocarbon group.

[0031] (A) When the hyaluronic acid derivative has steryl groups, the steryl groups in the hyaluronic acid derivative self-associate in water, and a single molecule or multiple molecules associate to form a nano-sized hydrogel.

[0032] [Steryl group] The term "steryl group" used herein is not particularly limited as long as it is a group having a steroid skeleton. Specific examples of steroids include cholesterol, cholestanol, campestanol, ergostanol, stigmastanol, coprostanol, stigmasterol, sitosterol, lanosterol, ergosterol, cimialenol, bile acids, testosterone, estradiol, progesterone, cortisol, cortisone, aldosterone, corticosterone, and deoxycortisterone. Examples of steryl groups include cholesteryl, stigmasteryl, lanosteryl, and ergosteryl groups, with cholesteryl groups (particularly cholest-5-en-3β-yl groups) being preferred.

[0033] [Steryl group introduction rate] The introduction rate of steryl group into (A) hyaluronic acid derivative (hereinafter sometimes simply referred to as "steryl group introduction rate") is preferably 5% or more and 60% or less, more preferably 10% or more and 60% or less, even more preferably 15% or more and 60% or less, even more preferably 20% or more and 45% or less, and particularly preferably 25% or more and 45% or less.By the introduction rate of steryl group being within the above range, (A) hyaluronic acid derivative can strongly interact with the hydrophobic part of poorly water-soluble drug.

[0034] The steryl group introduction rate is 1 It can be measured by H-NMR measurement. 1 It can be calculated based on the following formula using the integral value of the peak derived from the steryl group of (A) the hyaluronic acid derivative in the H-NMR spectrum and the integral value of the peak derived from the acetyl group of N-acetyl-D-glucosamine contained in (A) the hyaluronic acid derivative (COCH3, 1.6 ppm to 2.0 ppm, 3H). H represents the number of hydrogen atoms corresponding to the peak. Specifically, the measurement can be carried out, for example, according to the method described in the Examples below.

[0035] [Steryl group introduction rate] (%) = [(steryl group-derived peak integral value × 3 / n H ) / (peak integral value derived from the acetyl group of N-acetyl-D-glucosamine)] × 100

[0036] The average molecular weight of (A) hyaluronic acid derivative is sufficient as long as it is 3,000 (3k) or more and 40,000 (40k) or less, and can be adjusted appropriately according to the purpose and dosage form.For example, from the viewpoint of improving the sustained release function derived from diffusion delay in oral administration, (A) hyaluronic acid derivative with a relatively large molecular weight is preferred.On the other hand, when the final dosage form is a solution preparation, from the viewpoint of syringeability, (A) hyaluronic acid derivative with a relatively small molecular weight is preferred.

[0037] (A) The average molecular weight of hyaluronic acid derivative is preferably 7k or more but 38k or less, more preferably 8k or more but 35k or less, more preferably 8k or more but 30k or less, more preferably 8k or more but 20k or less, and particularly preferably 8k or more but 15k or less.By making the weight-average molecular weight of hyaluronic acid derivative below the upper limit value, it can suppress the increase of viscosity, and can dissolve the hyaluronic acid derivative in pharmaceutical composition at higher concentration.

[0038] The "average molecular weight of the hyaluronic acid derivative" referred to here is the weight average molecular weight determined by size exclusion chromatography multi-angle light scattering detector (SEC-MALS). The weight-average molecular weight of the hyaluronic acid derivative can generally be adjusted by using a raw material having a corresponding molecular weight.

[0039] Specific examples of preferred (A) hyaluronic acid derivatives include hyaluronic acid derivatives having one or more repeating units represented by the following general formula (I) (hereinafter, sometimes referred to as "repeating unit (I)").

[0040] [ka]

[0041] (In the formula, R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, formyl and C 1-6 alkylcarbonyl. Z represents a direct bond or a peptide linker consisting of any amino acid residues of 2 to 30. X 1 is -NR b -R, -NR b -COO-R, -NR b -CO-R, -NR b -CO-NR c-R, -COO-R, -O-COO-R, -SR, -CO-Y a -SR, -O-CO-Y b -SR, -NR b -CO-Y b It is a group selected from the group consisting of groups represented by -SR and -SSR. R a , R b and R c are each independently a hydrogen atom, C 1-20 Alkyl, Amino C 2-20 Alkyl and Hydroxy C 2-20 alkyl, where R a , R b and R c The alkyl portion of is -O- and -NR f A group selected from the group consisting of - may be inserted. R f is a hydrogen atom, C 1-12 Alkyl, Amino C 2-12 Alkyl and Hydroxy C 2-12 R is a group selected from the group consisting of alkyl. f The alkyl portion of the formula (I) may be inserted with a group selected from the group consisting of -O- and -NH-. R is a steryl group. Y is C 2-30 Alkylene, or -(CH2CH2O) m -CH2CH2-. Here, the alkylene of Y is -O-, -NR g A group selected from the group consisting of - and -SS- may be inserted. R g is a hydrogen atom, C 1-20 Alkyl, Amino C 2-20 Alkyl and Hydroxy C 2-20 R is a group selected from the group consisting of alkyl. g The alkyl portion of the formula (I) may be inserted with a group selected from the group consisting of -O- and -NH-. Y a is C 1-5 It is alkylene. Y b is C2-8 Alkylene or C 2-8 It is alkenylene. m is an integer between 1 and 100.

[0042] The hyaluronic acid derivative (A) preferably includes a hyaluronic acid derivative having one or more repeating units represented by the following general formula (Ia) (hereinafter, sometimes referred to as "repeating unit (Ia)").

[0043] [ka]

[0044] (In the formula, R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, formyl and C 1-6 X is a group selected from the group consisting of -NR a -Y-NR b -COO-R is a hydrophobic group. a and R b are each independently a hydrogen atom and C 1-6 alkyl; R is a steryl group; Y is C 2-30 Alkylene, or -(CH2CH2O) m -CH2CH2-, and m is an integer of 1 or more and 100 or less.

[0045] When the hyaluronic acid derivative contains two or more repeating units (I) or two or more repeating units (Ia), the repeating units may be the same or different.

[0046] The hyaluronic acid derivative may be modified at a position other than the repeating unit (I) or the repeating unit (Ia), for example, the hydroxy group may be modified by -O(C 1-6 alkyl), -O(formyl), -O(C 1-6The carboxy group may be converted to an amide or ester, or may form a salt.

[0047] Repeating Unit The group "-ZN(R a )YX 1 " is the formula: -NH-(CH2) mz -NH-R; -NH-(CH2) mz -NH-COO-R; -NH-(CH2CH2O) m -CH2CH2-NH-COO-R; -NH-(CH2) mz -COO-R; -NH-(CH2CH2O) m -CH2CH2-COO-R, -NH-(CH2) mz -O-COO-R; -NH-(CH2CH2O) m -CH2CH2-O-COO-R, -NH-(CH2) mz -SR; -NH-(CH2CH2O) m -CH2CH2-SR; -NH-(CH2) mz -O-CO-CH(R 8 )-CH2-SR; -NH-(CH2) mz -NHCO-CH(R 8 )-CH2-SR; -NH-(CH2CH2O) m -CH2CH2-NHCO-CH(R 8 )-CH2-SR; -NH-(CH2CH2O) m -CH2CH2-O-CO-CH(R 8 )-CH2-SR; -NH-(CH2) mz -SSR; and -Z-NR a -Y-NR b -COO-R (where mz is an integer between 2 and 30, and R 8 is a hydrogen atom or a methyl group, and R and m are as defined above in this specification. The group includes a group selected from the group consisting of groups represented by the formula: Examples of the group include: -NH-(CH2) mz -NH-COO-R; -NH-(CH2CH2O) m -CH2CH2-NH-COO-R; and -NH-(CH2) mz -SSR (wherein mz, ​​R, and m are as defined previously in this specification.) A group selected from the group consisting of: is preferred.

[0048] (Z) In general formula (I), Z is preferably a direct bond. In another embodiment, when Z is a peptide linker, X 1 Ha-NR b Preferably, Z is -COO-R. In another embodiment, Z is -NH-[CH(-Z a )-CONH] n-1 -CH(-Z a )-CO-, where n is an integer of 2 or more and 30 or less, and Z a are each independently H2N-CH(-Z a The peptide linker is attached to the carboxy group of the glucuronic acid moiety at the N-terminus and to the group -N(-R a )-YX 1Examples of amino acids that can be used as amino acid residues of the peptide linker include α-amino acids, such as natural (L-form) amino acids such as alanine, arginine, asparagine (Asn), aspartic acid, cysteine, glutamine, glutamic acid, glycine (Gly), histidine, isoleucine, leucine (Leu), lysine, methionine, phenylalanine (Phe), proline, serine, threonine, tryptophan, tyrosine, and valine, as well as D-forms thereof, and all α-amino acids, including synthetic amino acids, can be used. That is, Z a Examples of such linkers include -CH3, H2NC(NH)NH(CH2)3-, H2NCOCH2-, and the like. Furthermore, n Zs may be the same or different. n is an integer of 2 to 30, preferably 2 to 10, and more preferably 2 to 4. Preferred examples of peptide linkers include -Gly-Phe-Leu-Gly-, -Asn-Phe-Phe-, -Phe-Phe-, Phe-Gly-, and the like.

[0049] (Y) In the general formula (I), Y is —(CH) n1 -and-(CH2CH2O) m1 A group selected from the group consisting of -CH2CH2- (where n1 is an integer of 2 or more and 20 or less, preferably an integer of 2 or more and 15 or less, more preferably an integer of 2 or more and 12 or less, and even more preferably an integer of 2 or more and 6 or less; m1 is an integer of 1 or more and 4 or less) is preferred. Specifically, -(CH2)2-, -(CH2)6-, -(CH2)8-, -(CH2) 12 -, or -(CH2CH2O)2-CH2CH2- is preferred. From the viewpoint of realizing high solubility in pure water or at low salt concentrations and exhibiting high precipitate-forming ability at physiological salt concentrations, Y is preferably -(CH2)2-, -(CH2)6-, -(CH2)8-, or -(CH2) 12 A group selected from the group consisting of - is preferred, with -(CH2)6- being more preferred.

[0050] Y may be, for example, -CH2CH2O-CH2CH2-SS-CH2CH2O-CH2CH2-, -(CH2CH2O)2-CH2CH2-SS-CH2CH2O-CH2CH2-, -CH2CH2O-CH2CH2-SS-(CH2CH2O)2-CH2CH2-, -(CH2CH2O)2-CH2CH2-SS-(CH2CH2O)2-CH2CH2-, -(CH2CH2O)2-CH2CH2-SS-(CH2CH2O)2-CH2CH2-, and the like.

[0051] (Y a ) Y a is preferably -CH2- or -CH2-CH2-.

[0052] (Y b ) Y b As the alkyl group, -CH2-CH2-, -CH(CH3)CH2-, 2-butene-1,4-diyl, hepta-2,4-diene-1,6-diyl, or octa-2,4,6-triene-1,8-diyl is preferred, and -CH2-CH2- or -CH(CH3)CH2- is more preferred.

[0053] Group "-ZN(R a )YX 1" is exemplified by -NH-(CH2)2-NH-CO-cholesteryl, -NH-(CH2)4-NH-(CH2)3-NH-(CH2)3-NH-COO-cholesteryl, -NH-(CH2)3-NH-(CH2)4-NH-(CH2)3-NH-COO-cholesteryl, -NH-(CH2)4-NH-(CH2)3-NH-COO-cholesteryl, -NH-(CH2)4-NH-(CH2)3-NH-COO-cholesteryl, -NH-(CH2)4-N(-(CH2)3-NH2)-COO-cholesteryl, -NH-(CH2)3-NH-(CH2)4-N(-(C -NH-(CH)-NH-(CH)-COO-cholesteryl, -NH-(CH)-NH-(CH)-N(-(CH)-NH-(CH)-NH)-COO-cholesteryl, -NH-(CH)-NH-(CH)-N(-(CH)-NH)-CO-NH-cholesteryl, -NH-(CH)-NH-(CH)-N(-(CH)-NH)-CO-cholesteryl, -NH-(CH)-NH-(CH)-N(-(CH)-NH)-cholesteryl, and the like are preferred. a )YX 1 " as R a , R b and R c is a hydrogen atom, and Y is a linear C 2-30 Alkylene or -(CH2CH2O) m -CH2CH2-, and Y a However, linear C 1-5 alkylene, or Y b However, linear C 2-8 Alkylene or linear C 2-8 It is alkenylene.

[0054] Repeating unit (Ia) In the general formula (Ia), X is -NH-(CH2)2-NH-COO-cholesteryl, -NH-(CH2)6-NH-COO-cholesteryl, -NH-(CH2) 12-NH-COO-cholesteryl or -NH-(CH2CH2O)2-CH2CH2-NH-COO-cholesteryl is preferred, and -NH-(CH2)2-NH-COO-cholesteryl, -NH-(CH2)6-NH-COO-cholesteryl or -NH-(CH2CH2O)2-CH2CH2-NH-COO-cholesteryl is more preferred.

[0055] [Repeating units incorporating maleimide groups] (A) The hyaluronic acid derivative may contain, in addition to the repeating unit (I), a structural unit into which a maleimide group (N-maleimide group) has been introduced. The maleimide group may be directly bonded to the hyaluronic acid, or may be bonded via a linker. The linkers connected to the maleimide groups contained in one molecule of the hyaluronic acid derivative may all be the same linker, or may be linkers of different lengths or types.

[0056] The "linker" referred to here is a group in which a group reactive with a carboxy group and a group reactive with an NH group in a maleimide group are linked by a chain group. Examples of the group reactive with a carboxy group include an amino group and a hydroxyl group, and examples of the group reactive with an NH group in a maleimide group include a carboxy group and a hydroxyl group. Examples of the chain group include the same group as the chain group in the linker that links the hyaluronic acid derivative and the steryl group. In the hyaluronic acid derivative of this embodiment, it is preferred that at least a part of the carboxyl group in the glucuronic acid moiety and the hydroxyl group in the N-acetylglucosamine moiety are linked to the NH group in the maleimide group by a linker having a chain hydrocarbon group.

[0057] An example of a repeating unit into which a maleimide group has been introduced is a repeating unit represented by general formula (II) (hereinafter, sometimes referred to as "repeating unit (II)").

[0058] [ka]

[0059] (In the formula, R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, C 1-6 Alkyl, formyl and C 1-6 alkylcarbonyl. Z represents a direct bond or a peptide linker consisting of any amino acid residues of 2 to 30. X 2 is a maleimide group. R d is a hydrogen atom, C 1-20 Alkyl, Amino C 2-20 Alkyl and Hydroxy C 2-20 alkyl, and R d The alkyl portion of is -O- and -NR f A group selected from the group consisting of - may be inserted. R f is a hydrogen atom, C 1-12 Alkyl, Amino C 2-12 Alkyl and Hydroxy C 2-12 R is a group selected from the group consisting of alkyl. f The alkyl portion of the formula (I) may be inserted with a group selected from the group consisting of -O- and -NH-. Y is C 2-30 Alkylene, or -(CH2CH2O) m -CH2CH2-. Here, the alkylene of Y is -O-, -NR g A group selected from the group consisting of - and -SS- may be inserted. R g is a hydrogen atom, C 1-20 Alkyl, Amino C 2-20 Alkyl and Hydroxy C 2-20 R is a group selected from the group consisting of alkyl. g The alkyl portion of the formula (I) may be inserted with a group selected from the group consisting of -O- and -NH-. m is an integer between 1 and 100.

[0060] When the hyaluronic acid derivative (A) contains two or more repeating units (II), the repeating units may be the same or different. In another embodiment, the hyaluronic acid derivative (A) may be a hyaluronic acid derivative consisting essentially of the repeating unit (I), the repeating unit (Ia) and the repeating unit (II).

[0061] The repeating unit (II) is particularly a repeating unit represented by the general formula (II), in which Z is a direct bond and R d is a hydrogen atom or C 1-6 alkyl and Y is C 2-30 Alkylene or -(CH2CH2O) m -CH2CH2- and X 2 is a maleimide group; Z is a direct bond, and R d is a hydrogen atom or C 1-6 alkyl and Y is C 2-30 is alkylene, and X 2 is a maleimide group; Z is a direct bond and R d is a hydrogen atom and Y is C 2-30 is alkylene, and X 2 is a maleimide group; Z is a direct bond, and R d is a hydrogen atom and Y is C 2-10 is alkylene, and X 2 It is more preferable that the repeating unit is a maleimide group.

[0062] In the pharmaceutical composition of this embodiment, when the maleimide group is introduced into the (A) hyaluronic acid derivative, the introduction rate of the maleimide group into the hyaluronic acid derivative (hereinafter, sometimes simply referred to as "maleimide group introduction rate") is not particularly limited, but is preferably 1.0% or more, more preferably 3.0% or more, more preferably 5.0% or more, and even more preferably 10% or more. The introduction rate of the maleimide group into the (A) hyaluronic acid derivative is preferably 25% or less, more preferably 20% or less.

[0063] The maleimide group introduction rate is 1 It can be measured by H-NMR measurement. 1 The H-NMR spectrum is obtained by measuring a solution in which the hyaluronic acid derivative of this embodiment is dissolved in a heavy solvent 0.02N DCl DMSO-d6 / D2O mixed solution (2N DCl D2O:DMSO-d6=1:99). 1 The introduction rate of cholesteryl groups and maleimide groups to the hyaluronic acid unit is calculated using the integral value of the peak (COCH3, 1.6-2.0 ppm; 3H) derived from the acetyl group of the glucosamine portion of the hyaluronic acid derivative in the H-NMR spectrum, the integral value of the peak (CH3, 0.7 ppm; 3H) derived from the methyl group in the cholesteryl group, and the integral value of the peak (-CH=CH-, 6.9 ppm; 2H) derived from the maleimide group, according to the following formula: Note that the peak (5H) derived from cholesteryl groups overlaps with the peak near 1.6 to 2.0 ppm, which includes the peak derived from the acetyl group of the glucosamine moiety. Therefore, the value calculated by subtracting 5 / 3 times the integral value of the peak derived from the cholesteryl group methyl (0.7 ppm) from the integral value of the peak near 1.6 to 2.0 ppm (i.e., [[peak integral value (1.6 to 2.0 ppm)] - [peak integral value (0.7 ppm)] × 5 / 3]) is used as the integral value (corrected value) of the acetyl group derived from hyaluronic acid to calculate the introduction rate. First, the steryl group introduction rate (%) is calculated using the above formula.

[0064] Furthermore, the maleimide group introduction rate (%) can be calculated based on the following formula using the integral value of the peak derived from the maleimide group and the integral value of the peak derived from the cholesteryl group (COCH, 1.6 ppm to 2.0 ppm, 3H): Specifically, it can be measured according to the method described in the Examples below.

[0065] [Maleimide group introduction rate (%)] = ([Integrated peak value attributable to maleimide groups] × 3) / ([Integrated peak value attributable to steryl groups] × 2) × [Steryl group introduction rate (%)]

[0066] The content of the hyaluronic acid derivative (A) relative to the total amount of the pharmaceutical composition of this embodiment is preferably 1 mg / mL or more and less than 50 mg / mL, more preferably 3 mg / mL or more and 45 mg / mL or less, and even more preferably 5 mg / mL or more and 40 mg / mL or less.

[0067] (Method of producing hyaluronic acid derivatives) The hyaluronic acid derivative (A) contained in the pharmaceutical composition of this embodiment can be obtained, for example, by converting the carboxy group of glucuronic acid to an amide and introducing a steryl group directly or via a linker into at least a portion of the hyaluronic acid derivative. Alternatively, the hyaluronic acid derivative can be obtained by converting the carboxy group of glucuronic acid to an amide, introducing a steryl group directly or via a linker into at least a portion of the hyaluronic acid derivative, and introducing a maleimide group directly or via a linker into the remaining portion of the hyaluronic acid derivative. The steryl group introduction rate can be controlled by adjusting the amount of the compound having a steryl group to be reacted with the raw material hyaluronic acid or its derivative. The maleimide group introduction rate can be controlled by adjusting the amount of the compound having a maleimide group to be reacted. Methods for introducing maleimide groups or steryl groups into the raw material hyaluronic acid can be carried out by appropriately modifying the methods described in, for example, JP 2021-123597 A, JP 2022-013861 A, JP 2022-044579 A, ​​etc.

[0068] (A) When both a steryl group and a maleimide group are introduced into the hyaluronic acid derivative, the raw material hyaluronic acid may be reacted with a compound having a steryl group, and the resulting reaction product may be reacted with a compound having a maleimide group; the raw material hyaluronic acid may be reacted with a compound having a maleimide group, and the resulting reaction product may be reacted with a compound having a steryl group; or the raw material hyaluronic acid may be added to the reaction system together with a compound having a maleimide group and a compound having a steryl group, and reacted with the resulting reaction product.

[0069] A specific example of a method for converting the carboxy group of glucuronic acid to an amide and introducing a steryl group or maleimide group is to ion-exchange the starting hyaluronic acid or a derivative thereof with a tetraalkylammonium salt (e.g., tetrabutylammonium (TBA) salt), and then react the hyaluronic acid salt with an amine having a steryl group (particularly a cholesteryl group) in a solvent in the presence of a suitable condensing agent.

[0070] The condensing agent that can be used in the above reaction is not particularly limited, and examples thereof include 4-(4,6-dimethoxy-1,3,5-triazine)-4-methylmorpholinium (DMT-MM), N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 2-benzotriazole-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HODhbt), benzotriazole-1-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), and benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium. Examples include hexafluorophosphate (BOP), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and N-hydroxysuccinimide (NHS).

[0071] In particular, although not limited to, DMT-MM is preferred because the reaction proceeds efficiently even in a mixed solvent of water and an organic solvent.In addition, by using DMT-MM as a condensing agent, in a system where a large number of hydroxyl groups coexist, it is possible to suppress the formation of ester bonds and highly selectively form amide bonds between amino groups and carboxyl groups.The use of this condensing agent can, for example, prevent the reaction of the solvent alcohol with the carboxyl group of the hyaluronic acid moiety, or prevent the intramolecular or intermolecular bonding of the carboxyl group and the hydroxyl group simultaneously present in the hyaluronic acid moiety, resulting in the formation of undesired crosslinks.

[0072] Examples of solvents used in the steryl group introduction reaction include water, DMSO, methanol, ethanol, propanol, butanol, isopropanol, polyhydric alcohols, acetonitrile, DMF, THF, dichloromethane, chloroform, hexane, diethyl ether, ethyl acetate, and mixtures thereof. The polyhydric alcohol may be a dihydric alcohol or a trihydric alcohol. Examples of dihydric alcohols include ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, neopentyl glycol, 1,4-butanediol, and 1,6-hexanediol. Examples of trihydric alcohols include glycerin and trimethylolpropane.

[0073] In the production of hyaluronic acid derivatives into which both steryl and maleimide groups have been introduced, the pH of the reaction system is preferably acidic during the steryl group introduction reaction, whereas under basic conditions, succinimide groups may be generated by the deactivation of the maleimide groups.

[0074] Alternatively, the starting hyaluronic acid or its derivative can be ion-exchanged with a tetraalkylammonium salt (e.g., tetrabutylammonium (TBA) salt), and then react this hyaluronic acid salt with a spacer moiety in a solvent in the presence of a suitable condensing agent (at this time, protection and deprotection reactions can be carried out as necessary), converting the carboxyl group (-COOH) of the starting hyaluronic acid or its derivative, and then reacting it with a suitable reagent. Examples of the combination of groups derived from carboxyl groups and reaction reagents are shown below. -CONR a -Y-NR b H + Hal-R; -CONR a -Y-NR b H + Hal-COOR; -CONR a -Y-NR b H + HOCO-R; -CONR a -Y-NR bH + Hal-CO-R; -CONR a -Y-NR b -COOH + HNR c -R; -CONR a -Y-NR b -CO-NR c H + Hal-R; -CONR a -Y-NR b H + HOCO-NR c -R; -CONR a -Y-NR b H + Hal-CO-NR c -R; -CONR a -Y-COOH + HO-R; -CONR a -Y-OH + Hal-COO-R; -CONR a -Y-OCOOH + HO-R; -CONR a -Y-OCOOH + Hal-R; -CONR a -Y-OCO-Hal + HO-R; -CONR a -Y-SH + Hal-R; -CONR a -Y-Hal + HS-R; -CONR a -Y-CO-Y a -Hal + HS-R; -CONR a -Y-CO-Y a -SH + Hal-R; -CONR a -Y-O-CO-CH=CH2+ HS-R; -CONR a -Y-NR b -CO-CH(CH3)=CH2+ HS-R; -CONR a -Y-SH + HS-R; -COZ-OH + HNR a -Y-NR b-COO-R; -COZ-NR a -Y-NR b H + Hal-COO-R (In the formula, R a , R b , R c , Y, Y a , Y b and Z are as previously defined herein, and Hal represents a halogen atom selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom).

[0075] Examples of reaction modes include dehydrohalogenation reactions, condensation reactions, dehydration reactions, nucleophilic addition reactions such as Michael addition, and oxidative disulfide formation reactions. These are well-known reactions, and can be appropriately selected by those skilled in the art and carried out under preferred reaction conditions. When the conversion product or reaction product has a carboxy group, it may be converted into an N-hydroxysuccinimide (hereinafter also referred to as "NHS") ester and then reacted.

[0076] Another method is to react the carboxyl group of the raw material hyaluronic acid or its derivative with 2-aminoethyl 2-pyridyl disulfide to prepare a hyaluronic acid derivative having a spacer with a mercapto group modified with a leaving group at the end, and then subject this to a nucleophilic substitution reaction with thiocholesterol to form a disulfide bond.

[0077] Furthermore, the method of preparing the carboxyl group of hyaluronic acid or its derivatives that introduces a part of spacer, and the method of introducing a part of spacer into steryl group, and then reacting them.Some specific examples have been mentioned above, but when -SS- is inserted into Y, the carboxyl group of hyaluronic acid can also be prepared by introducing the spacer that has mercapto group at the end of the hyaluronic acid derivative, and the steryl group that has mercapto group at the end of the spacer, and then oxidatively react them to form disulfide bond.At this time, one mercapto group can be reacted with 2-mercaptopyridine to form disulfide, and then be replaced with the other mercapto group.

[0078] After preparing the hyaluronic acid derivative, other substituents may be introduced. For example, 0.1% to 95.0%, preferably 10% to 60%, of the carboxy groups in the hyaluronic acid derivative may be replaced with -CO-X z , where X z is the following group: -NH-(CH2) p1 -O-CO-C(R 17 )=CH2; -NH-(CH2) p1 -O-CO-CH(R 17 )-CH2-S-CH2-CH(OH)-CH(OH)-CH2-SH; -NH-(CH2) p1 -SH; -NH-(CH2) p1 -NH-CO-C(R 17 )=CH2; -NH-(CH2) p1 -NH-C(=NH)-(CH2)3-SH; -NH-(CH2) p1 -NH-CO-(CH2) r -SH; -NH-(CH2) p1 -NH-CO-CH(R 17 )-CH2-S-CH2-CH(OH)-CH(OH)-CH2-SH; -NH-(CH2) p1 -NH-CO-CH(NH2)-CH2-SH; -NH-(CH2) p1 -NH-CO-CH(NH2)-(CH2)2-SH; -NH-NH-CO-(CH2)4-CO-NH-NH-C(=NH)-(CH2)3-SH; -NH-(CH2-CH2-O) q -CH2-CH2-O-CO-C(R 17 )=CH2; -NH-(CH2-CH2-O) q -CH2-CH2-O-CO-CH(R 17 )-CH2-S-CH2-CH(OH)-CH(OH)-CH2-SH; -NH-(CH2-CH2-O) q -CH2-CH2-SH; -NH-(CH2-CH2-O) q -CH2-CH2-NH-CO-C(R 17 )=CH2; -NH-(CH2-CH2-O) q -CH2-CH2-NH-C(=NH)-(CH2)3-SH; -NH-(CH2-CH2-O) q -CH2-CH2-NH-CO-(CH2) r -SH; -NH-(CH2-CH2-O) q -CH2-CH2-NH-CO-CH(R 17 )-CH2-S-CH2-CH(OH)-CH(OH)-CH2-SH; -NH-(CH2-CH2-O) q -CH2-CH2-NH-CO-CH(NH2)-CH2-SH; -NH-(CH2-CH2-O) q -CH2-CH2-NH-CO-CH(NH2)-(CH2)2-SH; -NH-CH(CO2H)-(CH2)-SH; -NH-CH(COH)-(CH)-SH; and -NH-CH(CO2H)-(CH2)2-CONH-CH(CONH-CH2-CO2H)-CH2-SH (where R 17 is a hydrogen atom or C 1-6 p1 is an alkyl group, p2 is an integer of 2 or more and 10 or less, q is an integer of 1 or more and 200 or less, and r is an integer of 1 or more and 3 or less. It can also be converted to

[0079] (B) Active ingredient The pharmaceutical composition of this embodiment contains (A) a hyaluronic acid derivative and (B) an active ingredient. The (B) active ingredient in the pharmaceutical composition of this embodiment is a compound having a moiety that targets E3 ligase and a divalent group with a molecular weight of 70 to 300. Many moieties that target E3 ligase are poorly water-soluble, but the introduction of a divalent group with a molecular weight of 70 to 300 improves the water solubility of the complex with the (A) hyaluronic acid derivative. Hereinafter, the "divalent group with a molecular weight of 70 to 300" may be referred to as "divalent group B."

[0080] (B) The molecular weight of the divalent group B in the active ingredient is a value calculated from the molecular formula of the compound.

[0081] The "E3 ligase targeting site" in the (B) active ingredient is not particularly limited as long as it contains a structure that functions as a ligand for E3 ligase, and can be, for example, a structure containing a ligand for various E3 ligases. The E3 ligase ligand contained in the (B) active ingredient is not particularly limited, and can be appropriately selected from known E3 ligase ligands. E3 ligase ligands include, for example, small molecule ligands (i.e., having a molecular weight of less than 2000, 1000, 500, or 200 daltons). The small molecule may be non-peptidyl and may contain, for example, less than 4, 3, or 2 amino acids. Specific examples of known E3 ligase ligands include those disclosed in Non-Patent Document 2. (B) Examples of the "site that targets E3 ligase" in the active ingredient include VHL (von Hippel Lindau) ligand, CRBN (Cereblon) ligand, IAP ligand, MDM2 ligand, DCAF15 ligand, RNF114 ligand, KEAP1 ligand, etc.; examples of VHL ligand include VH032, VH010, VH298, and derivatives thereof. Examples of CRBN ligands include thalidomide (CAS No.: 50-35-1), lenalidomide (CAS No.: 191732-72-6), pomalidomide (CAS No.: 19171-19-8), TD106, and their derivatives; examples of IAP ligands include MeBS, LCL161, MV1, and their derivatives; examples of MDM2 ligands include nutlin-3a, idasanutlin, and their derivatives; examples of DCAF15 ligands include E7820 and their derivatives; examples of RNF114 ligands include EN219, nimbolide, and their derivatives; and examples of KEAP1 ligands include CDDO and their derivatives (Non-Patent Document 1). In the following chemical formula, the black circle indicates a site that can be directly or indirectly linked to the divalent group B. (B) The "site that targets E3 ligase" in the active ingredient preferably has a structure containing a VHL ligand or a CRBN ligand.

[0082] [ka]

[0083] The divalent group B in (B) the active ingredient is not particularly limited as long as it is a divalent group having a molecular weight of 70 to 300. Examples include alkylene groups, alkenylene groups, -C(=O)-, -NH-, -O-, -S-, and groups consisting of combinations thereof. Examples of groups consisting of such combinations include -C(=O)-O-, -OC(=O)-, -C(=O)NH-, -NH-C(=O)-, -NH-C(=O)-O-, -OC(=O)-NH-, -OP(=O)(OH)-O-, -OC 1-6 Alkylene group -, -OC 1-6 Alkylene groups -O-, -(OC 1-6 alkylene group)n- (n is an integer of 1 or more), or a group consisting of a combination thereof.

[0084] In view of the higher effect of improving the water solubility of the (B) active ingredient, the divalent group B in the (B) active ingredient is preferably one or more oxyalkylene groups having 1 to 6 carbon atoms (oxyC 1-6 A divalent group having 1 to 5 oxyC 1-6 A divalent group having an alkylene group is more preferred, and 2 to 5 oxy C 1-6 A divalent group having a group in which alkylene groups are linked in tandem is more preferred, and a divalent group having a group in which 2 to 5 oxyethylene groups are linked in tandem is even more preferred.

[0085] (B) The divalent group B in the active ingredient is also preferably a divalent group having a group in which two groups selected from the group consisting of aliphatic cyclic groups and aliphatic heterocyclic groups, or one group selected from the group consisting of aliphatic cyclic groups and aliphatic heterocyclic groups and one group selected from the group consisting of aryl groups and heteroaryl groups, are linked by an alkylene group having 1 to 6 carbon atoms. The aliphatic cyclic group is preferably a group in which two hydrogen atoms have been removed from a ring such as cyclopentane or cyclohexane. Examples of the aliphatic heterocyclic group include groups in which two hydrogen atoms have been removed from a ring such as tetrahydrofuran, pyrrolidine, tetrahydrothiophene, imidazolidine, oxazolidine, thiazolidine, tetrahydropyran, piperidine, thiane, piperazine, morpholine, thiomorpholine, dioxane, and dithiane, with groups in which two hydrogen atoms have been removed from pyrrolidine and piperidine being preferred. The aryl group is preferably a group in which two hydrogen atoms have been removed from benzene. Examples of heteroaryl groups include groups in which two hydrogen atoms have been removed from a ring of furan, thiophene, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, etc., and groups in which two hydrogen atoms have been removed from pyrrole, pyrazole, imidazole, pyridine, pyrimidine, or pyrazine are preferred. (B) The divalent group B in the active ingredient is one in which two groups selected from the group consisting of an aliphatic cyclic group and an aliphatic heterocyclic group are C 1-6 A divalent group having a group linked by an alkylene group, or a group in which either an aliphatic cyclic group or an aliphatic heterocyclic group and either an aryl group or a heteroaryl group are C 1-6 Divalent groups having groups linked by an alkylene group are preferred; groups having -pyrrolidine-CH2-piperidine-, -pyrrolidine-CH2-pyrrolidine-, -piperidine-CH2-piperidine-, -benzene-CH2-piperidine-, -benzene-CH2-pyrrolidine, pyridine-CH2-piperidine-, pyrimidine-CH2-piperidine-, pyrazine-CH2-piperidine- are more preferred.

[0086] The solubility-improving effect of the active ingredient (B) in the pharmaceutical composition of this embodiment depends mainly on the size and structure of the divalent group B. Therefore, the divalent group B may be present at any site in the active ingredient (B). For example, the divalent group B may be directly bonded to the "E3 ligase-targeting site" in the active ingredient (B), or another functional site may be present between the "E3 ligase-targeting site" and the divalent group B.

[0087] For example, the active ingredient (B) can be a compound in which an E3 ligase ligand is linked to one end of a divalent group B and a hydrogen atom or a monovalent organic group is linked to the other end of the divalent group B. The link between the divalent group B and the E3 ligase ligand or the monovalent organic group can be formed by forming a covalent bond between them, and can be synthesized by various chemical reactions.

[0088] The monovalent organic group linked to the other end of the divalent group B is not particularly limited, and various groups can be used. The monovalent organic group may be a group derived from a low molecular weight compound or a medium molecular weight compound, and may be a peptide or an oligonucleotide. A low molecular weight compound refers to a compound having a molecular weight of less than about 500 and other than nucleic acids, peptides, and proteins. A medium molecular weight compound refers to a compound having a molecular weight of about 500 to 5,000 that is neither a low molecular weight compound nor a high molecular weight compound (such as a protein with a molecular weight of 10,000 or more), and other than nucleic acids, peptides, and proteins.

[0089] As the (B) active ingredient, it is preferable to use a highly hydrophobic, i.e., poorly water-soluble, active ingredient, because the introduction of the divalent group B can more fully exhibit the effect of improving the solubility of the complex with the (A) hyaluronic acid derivative.In addition, "poorly water-soluble" refers to the drug that is classified as slightly soluble, slightly soluble, poorly soluble, very poorly soluble or almost insoluble among the drugs that are classified as very soluble, soluble, slightly soluble, slightly poorly soluble, poorly soluble, very poorly soluble or almost insoluble in the terms indicating solubility in the 17th revised Japanese Pharmacopoeia.

[0090] Specifically, the active ingredient (B) may be a poorly water-soluble drug having a solubility in water of 1 mg / mL or less. The pharmaceutical composition of the present embodiment can solubilize such poorly water-soluble drugs at high concentrations without using organic solvents and while reducing the amount of highly toxic surfactants used.

[0091] The molecular weight of (B) the active ingredient is preferably 200 or more, more preferably 300 or more, even more preferably 400 or more, 500 or more, and may be 600 or more, 700 or more, 800 or more, or 900 or more. The molecular weight of (B) the active ingredient may be 10,000 or less, 8,000 or less, 7,000 or less, or 5,000 or less, preferably 2,500 or less, more preferably 2,000 or less, and even more preferably 1,500 or less.

[0092] (B) The molecular weight of the active ingredient is a value calculated from the molecular formula of the compound.

[0093] The active ingredient (B) in the pharmaceutical composition of this embodiment is preferably a compound in which a moiety that targets E3 ligase and a moiety that binds to a target protein to be degraded by E3 ligase are linked by a divalent group B, since this more fully demonstrates the solubility-improving effect of the divalent group B. In the active ingredient (B), the "moiety that binds to a target protein to be degraded by E3 ligase" may be a group derived from a low-molecular-weight compound or a medium-molecular-weight compound, or may be a peptide or an oligonucleotide. Furthermore, the target protein to be degraded by E3 ligase is not particularly limited as long as it is a protein that can be degraded using the UPS, and may be various proteins such as enzymes, receptors, signal transduction factors, structural proteins, and transcription factors.

[0094] The active ingredient (B) in the pharmaceutical composition of this embodiment is preferably a proteolysis-inducing chimeric protein compound (PROTAC molecule). By complexing the poorly water-soluble PROTAC molecule as the active ingredient (B) with the hyaluronic acid derivative (A), the solubility of the PROTAC molecule is improved, and therefore the pharmaceutical composition of this embodiment containing this complex is expected to have higher bioavailability than pharmaceutical compositions using conventional PROTAC molecules as active ingredients.

[0095] (B) When the active ingredient is a PROTAC molecule, the target protein may be any protein whose degradation is expected to have a positive or beneficial effect on the condition or pathology of the subject. The target protein may be a structural protein, a receptor, an enzyme, a cell surface protein, or a protein involved in the integrative function of a cell. These proteins include proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, protein degradation, or biosynthesis; proteins with functions such as kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transducer (signal transducer) activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, intercellular communication, regulation of biological processes, development, cell differentiation, and response to stimuli; behavioral proteins; cell adhesion proteins; proteins involved in cell death; proteins involved in transport (including proteins with protein transporter activity, nuclear transport activity, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron carrier activity, virulence, chaperone regulatory activity, nucleic acid binding activity, transcriptional regulator activity, or translational regulator activity (including extracellular organization and biogenesis activity)).

[0096] The target proteins include B7.1 and B7, TIFR1m, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G protein (e.g., Gq), histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNFαR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus, 3C protease, herpes simplex virus-1 (HSV-1), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha-reductase inhibitor, angiotensin II, glycerin Neuropeptide receptors, noradrenaline reuptake receptors, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor for NGF, beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 The compound may be a protein selected from the group consisting of neu, telomerase inhibitor, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel; acetyl-CoA carboxylase, adenylsuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvushimate phosphate synthase, or a compound that targets a human BET bromodomain-containing protein. For example, target proteins to be degraded by E3 ligase include kinases such as IRAK4 (interleukin-1 receptor-associated kinase 4), BTK (Bruton's tyrosine kinase), TRK (tropomyosin receptor kinase), and JAK family proteins; receptors such as androgen receptor (AR), estrogen receptor (ER), and epidermal growth factor receptor (EGFR); transcription factors such as IKAROS transcription factor family proteins and STAT3; and Bcl family proteins (Bcl-2, Bcl-X). LThe target proteins can be various proteins, such as apoptosis regulators such as BET family proteins (BRD2, BRD3, BRD4, BRD9, etc.); and epigenetic regulators such as BET family proteins (BRD2, BRD3, BRD4, BRD9, etc.). The active ingredient (B) in the pharmaceutical composition of this embodiment is preferably a compound having a site that binds to a protein selected from the group consisting of an androgen receptor, an estrogen receptor, a BET family protein, an IKAROS transcription factor family protein, and a Bcl family protein.

[0097] In the pharmaceutical composition of this embodiment, a molecule in which the ligand moiety of E3 ligase and the site binding to the target protein to be degraded by the E3 ligase are linked by a divalent group B can be used as the active ingredient (B). The active ingredient (B) in the pharmaceutical composition of this embodiment is a known PROTAC molecule or a modified compound thereof, in particular a molecule in which the ligand moiety of E3 ligase and the site binding to the target protein to be degraded by the E3 ligase are linked by one or more oxy-C 1-6 a divalent group having an alkylene group, or two or more selected from the group consisting of an aliphatic cyclic group and an aliphatic heterocyclic group are C 1-6 A PROTAC molecule linked by a divalent group having a group linked by an alkylene group is preferred; the ligand portion of the E3 ligase and the site binding to the target protein to be degraded by the E3 ligase are preferably 1 to 5 oxy C 1-6 a divalent group having an alkylene group, or two or more selected from the group consisting of cyclopentane, cyclohexane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, imidazolidine, oxazolidine, thiazolidine, tetrahydropyran, piperidine, thiane, piperazine, morpholine, thiomorpholine, dioxane, and dithiane are C 1-6 A divalent group having a group linked by an alkylene group is more preferred; and a divalent group having 2 to 5 oxy Cs between the ligand portion of E3 ligase and the site that binds to the target protein to be degraded by the E3 ligase is more preferred. 1-6More preferred is a divalent group having a group in which alkylene groups are linked in tandem, or a group having one selected from the group consisting of -pyrrolidine-CH2-piperidine-, -pyrrolidine-CH2-pyrrolidine-, and -piperidine-CH2-piperidine-; and more preferred is a group in which the ligand moiety of E3 ligase and the site binding to the target protein to be degraded by the E3 ligase are formed by a bond having 2 to 5 oxy-C 1-6 A divalent group having a group in which alkylene groups are linked in tandem is particularly preferred.

[0098] In the pharmaceutical composition of this embodiment, known PROTAC molecules or modified compounds thereof that contain the divalent group B according to the present invention in the site that binds to the target protein to be degraded by E3 ligase can also be used as the active ingredient (B). PROTAC molecules in which the site that binds to the target protein to be degraded by E3 ligase originally has a structure that contains the divalent group B are preferred because they exhibit a stronger solubility-improving effect of the (A) hyaluronic acid derivative than PROTAC molecules that do not have the divalent group B.

[0099] Examples of the active ingredient (B) in the pharmaceutical composition of this embodiment include ARV-825 (CAS number: 1818885-28-7), MZ-1 (CAS number: 1797406-69-9), ARCC-4 (CAS number: 1973403-00-7), ITRI-90, ARV-110 (CAS number: 2222112-77-6), ARV-471 (CAS number: 2229711-68-4), ARV-766 (CAS number: 2750830-09-0), NX-2127 (CAS number: 2416131-46-7), CC220 (CAS number: 1323403-33-3), and DT2216 (CAS number: 2365172-42-3).

[0100] In the pharmaceutical composition of this embodiment, a compound of a known PROTAC molecule or a modified compound thereof, in which the linking moiety that links the ligand moiety of E3 ligase to the site that binds to the target protein to be degraded by the E3 ligase is substituted with the divalent group B according to the present invention, can also be used as the active ingredient (B). The active ingredient (B) in the pharmaceutical composition of this embodiment is a known PROTAC molecule or a modified compound thereof, in which the linking moiety that links the ligand moiety of E3 ligase to the site that binds to the target protein to be degraded by the E3 ligase is substituted with one or more oxy-C 1-6 a divalent group having an alkylene group, or two or more selected from the group consisting of an aliphatic cyclic group and an aliphatic heterocyclic group are C 1-6 A PROTAC molecule substituted with a divalent group having a group linked by an alkylene group is preferred; the linker between the ligand portion of the E3 ligase and the site that binds to the target protein to be degraded by the E3 ligase has 1 to 5 oxy C 1-6 a divalent group having an alkylene group, or two or more selected from the group consisting of cyclopentane, cyclohexane, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, imidazolidine, oxazolidine, thiazolidine, tetrahydropyran, piperidine, thiane, piperazine, morpholine, thiomorpholine, dioxane, and dithiane are C 1-6 More preferred is a PROTAC molecule substituted with a divalent group having a group linked by an alkylene group; the linker between the ligand portion of the E3 ligase and the site that binds to the target protein to be degraded by the E3 ligase has 2 to 5 oxy Cs. 1-6 More preferred are PROTAC molecules substituted with a divalent group having a group in which alkylene groups are linked in tandem, or a group having one selected from the group consisting of -pyrrolidine-CH2-piperidine-, -pyrrolidine-CH2-pyrrolidine-, and -piperidine-CH2-piperidine-; and a PROTAC molecule in which the linkage between the ligand moiety of E3 ligase and the site binding to the target protein to be degraded by the E3 ligase is such that ... 1-6Even more preferred are PROTAC molecules in which the alkylene group is substituted with a divalent group having tandemly linked groups.

[0101] In the pharmaceutical composition of this embodiment, a compound obtained by modifying a known PROTAC molecule or a modified compound thereof by adding a divalent group B according to the present invention to the ligand moiety of E3 ligase or the site that binds to a target protein to be degraded by the E3 ligase can also be used as the active ingredient (B). The link between the divalent group B and the ligand moiety of E3 ligase or the site that binds to a target protein can be achieved by forming a covalent bond between them, and can be synthesized by various chemical reactions.

[0102] In this embodiment, the content of (B) active ingredient relative to 100 mass parts of (A) hyaluronic acid derivative is not particularly limited, and is appropriately determined in consideration of the type of (B) active ingredient, the molecular weight of (A) hyaluronic acid derivative, the introduction rate of steryl group, etc. In this embodiment, the content of (B) active ingredient relative to 100 mass parts of (A) hyaluronic acid derivative is preferably 1.0 mass parts or more, more preferably 2.0 mass parts or more.In this embodiment, the content of (B) active ingredient relative to 100 mass parts of (A) hyaluronic acid derivative can be 10,000 mass parts or less, preferably 1,000 mass parts or less, more preferably 100 mass parts or less, even more preferably 75 mass parts or less, and even more preferably 50 mass parts or less.

[0103] (B) The poorly water-soluble drug as the active ingredient may be blended singly or in combination of two or more.

[0104] The pharmaceutical composition of this embodiment can solubilize the active ingredient (B), which is a poorly water-soluble drug, without using an organic solvent when formulating it, thereby reducing the need for conventional, highly toxic solubilizing agents. Note that the desired effect may be achieved by a mechanism different from the above-mentioned mechanism. In other words, the hyaluronic acid derivative pharmaceutical composition of this embodiment can also be said to be an organic solvent-free composition.

[0105] <Other additives> The pharmaceutical composition of this embodiment may consist solely of (A) a hyaluronic acid derivative and (B) an active ingredient, or may contain other additives in addition to these. The other additives are not particularly limited as long as they are pharmacologically acceptable additives, and may be appropriately selected depending on the dosage form. Examples of such additives include water or other physiologically acceptable liquids (e.g., saline, phosphate-buffered saline (PBS)), vehicles, buffers, surfactants, pH adjusters, isotonicity agents, thickeners, excipients, binders, disintegrants, preservatives, stabilizers, cryoprotectants, colorants, etc. These additives may be used alone or in combination of two or more of the same or different additives.

[0106] Examples of buffering agents include Tris, sodium citrate hydrate, sodium acetate hydrate, sodium bicarbonate, dry sodium carbonate, sodium carbonate, magnesium sulfate, trometamol, boric acid, borax, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and histidine.

[0107] Surfactants can also be used as agents for promoting the association of the hyaluronic acid derivative (A). Examples of such surfactants include polysorbates, polyoxyethylene fatty acid esters, and cremophor.

[0108] Examples of pH adjusters include hydrochloric acid and sodium hydroxide. Examples of isotonic agents include potassium chloride, calcium chloride, sodium chloride, concentrated glycerin, glucose, D-mannitol, and the like. Examples of thickening agents include carboxyvinyl polymer, povidone, polyvinyl alcohol (partially saponified), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hypromellose, methyl cellulose, and glycerin.

[0109] Examples of preservatives include benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, sorbic acid, and alkylpolyaminoethylglycine. Examples of stabilizers include sodium edetate hydrate and polyvinylpyrrolidone (povidone).

[0110] The cryoprotectant is not particularly limited as long as it is known as a "cryoprotectant" or "lyoprotectant," and examples thereof include disaccharides, sorbitol, dextran, polyethylene glycol, propylene glycol, glycerin, glycerol, polyvinylpyrrolidone, dimethyl sulfoxide, etc.

[0111] Disaccharide is not particularly limited, and for example, can be sucrose, lactulose, lactose, maltose, trehalose, cellobiose, kojibiose, nigerose, isomaltose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiulose, mannobiose, melibiose, melibiulose, neolactose, galactosucrose, scillabiose, neohesperidose, rutinose, rutinulose, vicianose, xylobiose, primeverose etc.Among them, sucrose, trehalose, maltose or lactose are preferred, because they are widely used as cryoprotective agent.In addition, sucrose is more preferred, because of its use as pharmaceutical additive and from the viewpoint of more effectively suppressing the increase in particle size of the microparticles formed by hyaluronic acid derivative during freeze-drying.

[0112] Examples of excipients include cellulose, starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, powdered gum arabic, alginic acid, sodium alginate, pregelatinized starch, pumice granules, inositol, ethylcellulose, ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice granules, carmellose, carmellose sodium, hydrated silicon dioxide, dry yeast, dried aluminum hydroxide gel, dried sodium sulfate, dried magnesium sulfate, agar, and kaolin. Ingredients: cetethane powder, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, genmai koji, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat germ flour, rice flour, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower Ingredients: oil, white beeswax, zinc oxide, titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, calcined gypsum, sucrose fatty acid ester, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitate, magnesium hydroxide, squalane, stearyl alcohol, stearic acid, calcium stearate, polyoxyethylene stearate, magnesium stearate, dimethicone Hardened oil, refined gelatin, refined shellac, refined white sugar, refined white sugar spherical granules, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, tricalcium phosphate, soybean oil, soybean unsaponifiables, soybean lecithin, skim milk powder, talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate, tragacanth powder, silicon dioxide, calcium lactate, Perfiller 101, white shellac,White petrolatum, Hakudo, white sugar, white sugar and starch spherical granules, naked barley leaf extract powder, dried naked malt leaf green juice powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose syrup, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polystyrene Examples of suitable soluble calcium carbonates include sodium phosphate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, maltose, starch syrup, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methylcellulose, cottonseed flour, cottonseed oil, Japan wax, aluminum monostearate, glycerin monostearate, sorbitan monostearate, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular cornstarch starch, liquid paraffin, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate.

[0113] Examples of binders include sugars such as sucrose, fructose, lactose or lactose hydrate, fructooligosaccharides, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered candy, isomerized lactose, and honey sugar; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, and lactitol; water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate, and gum arabic; celluloses such as hydroxypropyl cellulose and methyl cellulose; starches such as corn starch, potato starch, rice starch, pregelatinized starch, and starch paste; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol; and inorganic compounds such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, and magnesium aluminosilicate.

[0114] Examples of disintegrants include celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; starches such as carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, potato starch, pregelatinized starch, and partially pregelatinized starch; and synthetic polymers such as crospovidone and crospovidone copolymer.

[0115] ≪Form≫ The dosage form of the pharmaceutical composition of this embodiment is not particularly limited and can be determined appropriately depending on the route of administration. For example, the pharmaceutical composition of this embodiment can be in the form of a solid, semi-solid, or liquid. In the case of solids, examples include forms such as powder, granules, pills, pellets, tablets, and capsules. In the case of a semi-solid, examples include gels, creams, and the like. In the case of a liquid, examples include a suspension in which a complex of (A) a hyaluronic acid derivative and (B) an active ingredient is diluted or suspended in water or a buffer solution such as phosphate buffer (PB) or phosphate buffered saline (PBS).

[0116] In the pharmaceutical composition of this embodiment, the complex of (A) hyaluronic acid derivative and (B) active ingredient may be nanoparticles or amorphous. When the complex is nanoparticles, the nanoparticles may be dispersed in water or other physiologically acceptable liquid to form a suspension, or the nanoparticles may be freeze-dried in the presence of a cryoprotectant to form a powder, which can be used as a raw material to form granules, tablets, or capsules. When the complex is amorphous, the amorphous may be dispersed or dissolved in water or other physiologically acceptable liquid to form a liquid, or the amorphous dried powder can be used as a raw material to form granules, tablets, or capsules. Whether the active ingredient (B) in the pharmaceutical composition of this embodiment is amorphous can be determined by differential scanning calorimetry (DSC) measurement.

[0117] ≪Manufacturing method≫ The pharmaceutical composition of this embodiment can be produced, for example, by mixing a solution (solution (A)) in which a hyaluronic acid derivative (A) has been dissolved with a solution (solution (B)) in which an active ingredient (B) has been dissolved, thereby forming a complex between the hyaluronic acid derivative (A) and the active ingredient (B). Solution (A) is prepared by dissolving the hyaluronic acid derivative (A) in water, PBS, or the like. Solution (B) can be prepared by dissolving the active ingredient (B) in a solution prepared by adding a solubilizing agent such as various organic solvents or vehicles to water. Simply mixing and stirring the two solutions forms a complex between the hyaluronic acid derivative (A) and the active ingredient (B) due to the interaction between the hydrophobic moiety, such as a steryl group, in the hyaluronic acid derivative (A) and the hydrophobic moiety in the active ingredient (B), or due to self-assembly of the hyaluronic acid derivatives themselves.

[0118] In the pharmaceutical composition of this embodiment, when the amount of (A) hyaluronic acid derivative is relatively large relative to the amount of (B) active ingredient, (A) hyaluronic acid derivative is likely to form nanoparticles that contain (B) active ingredient.For example, by making the amount of (A) hyaluronic acid derivative and (B) active ingredient in the solution during complex formation 10 mass parts or more and less than 30 mass parts, preferably 10 mass parts or more and 25 mass parts or less, more preferably 10 mass parts or more and 20 mass parts or less, the complex of (A) hyaluronic acid derivative and (B) active ingredient can be formed as nanoparticles.

[0119] When the amount of (A) hyaluronic acid derivative is relatively small relative to (B) active ingredient, (B) active ingredient and (A) hyaluronic acid derivative are likely to form amorphous.For example, by making the amount of (A) hyaluronic acid derivative and (B) active ingredient in the solution during complex formation be 30 mass parts or more and less than 100,000 mass parts, preferably 30 mass parts or more and 1000 mass parts or less, more preferably 30 mass parts or more and 100 mass parts or less, can form the complex that (B) active ingredient is kept as amorphous.

[0120] The complex formed in the solution can also be dried and powdered.Drying methods include, for example, ventilation drying, drying in a thermostatic oven, drying under reduced pressure, hot air circulation drying, freeze-drying, etc.Among them, freeze-drying is preferred.When the complex of (A) hyaluronic acid derivative and (B) active ingredient is in the form of nanoparticles, it is preferred to further include a cryoprotectant when freeze-drying.

[0121] The apparatus used for freeze-drying is not particularly limited, and for example, a commercially available freeze-dryer can be used. Among them, from the viewpoint of controlling the degree of vacuum, a freeze-dryer capable of monitoring the degree of vacuum inside the apparatus during freeze-drying is preferred, and from the viewpoint of controlling the product temperature, a tray-type freeze-dryer is preferred.

[0122] <Administration method> The pharmaceutical composition of this embodiment can be administered to animals classified as mammals, including humans (monkeys, marmosets, mice, rats, cows, horses, cats, dogs, pigs, sheep, goats, rabbits, etc.).

[0123] The administration route of the pharmaceutical composition of this embodiment is not particularly limited, and any currently known administration route can be used appropriately depending on the intended use, the location of the tissue to be treated, and the like. For example, administration routes include subcutaneous administration, intramuscular administration, intravenous administration, intra-arterial administration, intrathecal administration, intracerebral administration, intra-articular administration, intraperitoneal administration, intravaginal administration, intravesical administration, intrarectal administration, intravitreal administration, periocular administration, intradermal administration, intraperitoneal administration, intranasal administration, transbronchial administration, transpulmonary administration, transdermal administration, sublingual administration, oral administration, buccal administration, and eye drop administration.

[0124] The dosage of the pharmaceutical composition of this embodiment can be appropriately selected taking into consideration the type of subject (including age, sex, etc.). Generally, for example, in a human (body weight 60 kg), the daily dosage can be 0.01 μg to 20 mg, 0.1 μg to 15 mg, or 1 μg to 10 mg of the active ingredient (B). The dosage can be administered once a day or in divided doses twice or more per day.

[0125] The administration frequency may be a single administration of the above-mentioned dosage, or multiple administrations of the above-mentioned dosage, such as once every day, every two days, four days, one week, two weeks, three weeks, four weeks, one month, two months, three months, or six months, etc. Alternatively, administration may be performed at two or more sites in a single administration.

[0126] Other Embodiments In one embodiment, the present invention provides a method for preventing or treating a disease, which comprises administering an effective amount of the pharmaceutical composition to a human or animal patient. Furthermore, the term "effective amount" as used herein includes an amount effective for prevention or treatment, that is, an amount suitable for preventing the onset or treatment of the above-mentioned diseases.

[0127] In one embodiment, the present invention provides a composition for preventing or treating one or more diseases selected from the group consisting of cancer, infectious diseases, immune diseases, inflammatory disorders, allergic diseases, skin diseases, hypertension, diabetes, neurological diseases, genetic diseases, cardiovascular diseases, cerebrovascular diseases, respiratory diseases, eye diseases, ear diseases, and bone and joint diseases, comprising the active ingredient-hyaluronic acid derivative complex. The pharmaceutical composition of this embodiment is preferably used in a method for treating or preventing diseases using TPD.

[0128] The pharmaceutical composition of this embodiment is preferably used for the treatment or prevention of any pathological condition or state in which protein dysregulation (i.e., increased levels of the protein expressed in a patient) occurs and degradation of the abnormal protein in a patient would provide beneficial treatment or symptomatic relief to a patient in need thereof, including, for example, neurodegeneration, Huntington's disease and muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, spinal cord and brain injuries, seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulas, headaches, memory disorders, peripheral neuropathy, postherpetic neuralgia, spinal cord tumors, and stroke.

[0129] As used herein, the term "neurological disorder" refers to any disorder, disease, and / or syndrome caused by or resulting from neurological, psychiatric, psychological, and / or cerebrovascular manifestations or origins. The term "neurological disorder" as used herein also refers to a disease, disorder, or condition of the brain and nervous system, or a mental disorder or condition. Neurological disorders include, but are not limited to, the following: septum pellucidum defect, acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Adie pupil, Adie syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, AIDS-neurological complications, Alexander disease, Alpers syndrome, alternating hemiplegia of childhood, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, aneurysm, Angelman syndrome, hemangiomatosis, anoxia, and aphasia. syndrome, apraxia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia, dyspraxia, telangiectasia, ataxia and cerebellar degeneration / spinocerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Barth syndrome, Batten disease, Becker myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Bernhard-Troth syndrome, Binswanger's disease, Blepharospasm, Bloch-Sulzberger syndrome, brachial plexus birth trauma, traumatic brachial plexus palsy, pure autonomic dysfunction, brain and spinal cord tumors, cerebral aneurysms, cerebral trauma, Brown-Séquard syndrome, spinal-bulbar muscular atrophy, Canavan disease, carpal tunnel syndrome, causalgia, cavernoma, cavernous hemangioma, cavernous vascular malformation, central cervical spinal cord syndrome, central spinal cord syndrome, central pain syndrome, head injury, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysms, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral megalomania encephalomyelitis, cerebral hypoxia, cerebral palsy, cerebro-oculo-facial-skeletal syndrome, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chorea acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic hypotension, chronic pain, Cockayne syndrome type II, Coffin-Lowry syndrome, COFS, agenesis of the corpus callosum, coma and persistent vegetative state, complex regional pain syndrome, congenital bilateral facial palsy, congenital myasthenia, congenital myopathy, congenital cavernous vascularCavernous, malformations, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disease, Cushing's syndrome, megacytoplasmic inclusion disease, cytomegalovirus infection, opsoclonus-myoclonus syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, deep brain stimulation for Parkinson's disease, brachial plexus neuropathy, dementia, multi-infarct dementia, semantic dementia, subcortical dementia, dementia with Lewy bodies, myoclonic cerebellar synkinesis disorder, dentatorubral atrophy, dermatomyositis, developmental apraxiaDyspraxia), Devic's disease, diabetic neuropathy, diffuse sclerosis, autonomic nervous system imbalance, dysgraphia, dyslexia, dysphagia, dyspraxia, dyspraxia, myoclonic dyssynergia, progressive cerebellar dyssynergia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis lethargica, encephalopathy, trigeminal nerve region angiomatosis, epilepsy, upper and lower paralysis, Erb's palsy, Fabry's disease, Fahr's disease, syncope, Familial dysautonomia, familial hemangioma, familial basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile seizures, Fisher syndrome, floppy infant syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher disease, Gerstmann syndrome, Gerstmann-Straussler-Scheinker disease, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, glossopharyngeal neuralgia, Guillain-Barré syndrome , Hallervorden-Spatz disease, head injury, headache, persistent hemicrania, hemifacial spasm, alternating hemiplegia, hereditary neuropathy, hereditary spastic paraplegia, polyneuropathy-type hereditary ataxia, herpes zoster, otic varicella, Hirayama syndrome, Holmes-Adie syndrome, holoprosencephaly, HTLV-1-associated myelopathy, Huntington's disease, hydroanencephaly, hydrocephalus, normal pressure hydrocephalus, hydromyelopathy, hyperactivity, hyperadrenocorticism, hypersomnia, hypertonia, hypotension Infancy, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, childhood hypotonia, childhood neuroaxonal dystrophy, childhood phytanic acid storage disease, childhood Refsum's disease, childhood convulsions, inflammatory myopathy, foramen occipitalis, intestinal lipodystrophy, intracranial cyst, increased intracranial pressure, Isaac's syndrome, Joubert's syndrome, Kearns-Sayre syndrome, Kennedy's disease, opsoclonus-myoclonus syndrome (Kinsbourne syndrome)syndrome), Kleine-Lewin syndrome, Klippel-Feil syndrome, Klippel-Trenaunay-Weber syndrome (KTS), Klüver-Bucy syndrome, Korsakoff amnesic syndrome, Krabbe disease, Kugelberg-Welander disease, Kuhl, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral femoral cutaneous nerve entrapment, lateral cord syndrome, learning disability, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, cerebral white matter Atrophy, Levine-Critchley syndrome, Dementia with Lewy bodies, Lipid storage disease, Lichenary defects, Locked-in syndrome, Lou Gehrig's disease, Lupus erythematosus - neurological type, Sequelae, Lyme disease - neurological type, Complications, Machado-Joseph disease, Encephalopathy, Mania, Megalencephaly, Melkerson-Rosenthal syndrome, Meningitis, Meningitis and encephalitis, Menkes disease, Dysesthesias femoral neuralgia, Metachromatic type, Leukodystrophy, Microcephaly, Migraine, Miller Fisher syndrome, Minor stroke, Mitochondria Amyopathy, Moebius syndrome, Hirayama disease, Motor neuron disease, Moyamoya disease, Mucolipidoses, Mucopolysaccharidosis, Multifocal motor neuropathy, Multi-infarct dementia, Multiple sclerosis, Multiple system atrophy, Multiple system atrophy with orthostatic hypotension, Muscular dystrophy, Myasthenia - congenital, Myasthenia gravis, Demyelinating diffuse sclerosis, Myoclonic encephalopathy of childhood, Myoclonus, Myopathy, Myopathy - congenital, Myopathy - thyrotoxicosis, Myotonia, Congenital Neuromyotonia, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with cerebral iron accumulation, Neurofibromatosis, Neuroleptic malignant syndrome, Neurological complications of AIDS, Neurological complications of Lyme disease, Neurological effects of cytomegalovirus infection, Neurological manifestations of Pompe disease, Neurological sequelae of lupus erythematosus, Neuromyelitis optica, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorder, Neuropathy - hereditary, Neurosarcoidosis, Neurotoxicity, Nevus cavernosus, Niemann-Pick disease, Normal pressure hydrocephalus, Occipital neuralgia, Obesity, Split cord, Ohtahara syndrome, Olivopontocerebellar atrophy, Ocular myoclonus, Orthostatic hypotension, O'Sullivan-McLeod syndromeSyndrome, Overuse Syndrome, Chronic Pain, Pain, Pantothenate Kinase-Related Neurodegeneration, Paraneoplastic Syndrome, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Migraine, Facial Hemiatrophy, Pelizaeus-Merzbacher Disease, Pena-Shocker Syndrome Type II, Perineural Cyst, Periodic Paralysis, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorder, Phytanic Acid Storage Disease, Pick's Disease, Stiff Neck, Piriformis Syndrome, Pituitary Tumor, Polymyositis, Pompe Disease, Porencephaly, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postpolio Syndrome, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, Primary Dentate Atrophy Atrophy), primary lateral sclerosis, primary progressive aphasia, prion disease, progressive hemifacial atrophy, progressive gait ataxia, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, Ramsay Hunt syndrome I (obsolete name), Ramsay Hunt syndrome II (obsolete name), Rasmussen encephalitis, reflex sympathetic dystrophy syndrome, Refsum disease, Refsum disease - childhood type, repetitive movement disorder, repetitive strain injury, restless legs syndrome, retroviral-associated myelopathy, Rett syndrome, Reye syndrome, Relay-Day syndrome, sacral nerve root cyst, chorea, salivary gland disease, Sandhoff disease, Schilder's disease, schizencephaly, Seitelberger's disease, seizure disorders, semantic dementia, septo-optic dysplasia, shaken baby syndrome, shingles, Scheid-Rager syndrome, Sjogren's syndrome, sleep apnea syndrome, African sleeping sickness, Sotos disease, spasticity, spina bifida, spinal cord infarction, spinal cord injury, spinal tumor, spinal muscular atrophy, spinocerebellar atrophy, spinocerebellar degeneration, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, striatonigral degeneration, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache, dysphagia (SUNCT) Headache Swallowing Disorders, Sydenham's chorea, syncope, syphilitic spinal sclerosis, syringomyelia, syringomyelia, systemic lupus erythematosus, tabes dorsalis, tardive dyskinesia, Tarlov's cyst, Tay-Sachs disease, temporal arteritis, tethered cord syndrome, Thomsen's myotoniaMyotonia, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Trigeminal Neuralgia, Todd's Palsy, Tourette's Syndrome, Transient Ischemic Attack, Transmitting Spongiform Encephalopathy, Transverse Myelitis, Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitis including Temporal Arteritis, von Echonomo Disease, von Hippel-Lindau Disease (VHL), von Recklinghausen Disease, Wallenberg Syndrome, Werdnig-Hoffmann Disease, Wernicke-Korsakoff Syndrome, West Syndrome, Whipple's Disease, Williams Syndrome, Wilson's Disease, X-linked Spinal-Bulbar Muscular Atrophy, or Zellberger Syndrome.

[0130] In one embodiment, the present invention provides use of the above-mentioned active ingredient-hyaluronic acid derivative complex for the manufacture of a pharmaceutical composition.

[0131] <Method for improving the solubility of poorly water-soluble drugs in water> As mentioned above, by introducing a divalent group B into a poorly water-soluble drug, the solubility of the complex of the poorly water-soluble drug and the hyaluronic acid derivative into which a steryl group has been introduced is improved.That is, the method for improving the solubility of a poorly water-soluble drug in water in this embodiment (hereinafter sometimes abbreviated as "solubility improvement method") is to introduce a poorly water-soluble drug into which a molecular weight of 70 to 300 and a C of 1 to 5 are introduced. 1-6 This method involves introducing a structure having an oxyalkylene group, and then complexing the resulting oxyalkylene group-containing poorly water-soluble drug with a hyaluronic acid derivative into which a steryl group has been introduced.

[0132] The "hyaluronic acid derivative into which a steryl group has been introduced" used in the solubility improving method of this embodiment is the same as the above-mentioned "hyaluronic acid derivative (A)."

[0133] The "molecular weight of 70 or more and 300 or less and C1 or more and 5 or less" used in the solubility improving method of this embodiment 1-6The "structure having an oxyalkylene group" is the same as the above-mentioned "divalent group B". In the solubility improvement method of the present embodiment, the "structure having a molecular weight of 70 or more and 300 or less and having 1 or more and 5 or less C 1-6 As a preferable structure of the "structure having an oxyalkylene group", the divalent groups that were considered preferable as the divalent group B in the (B) active ingredient in the pharmaceutical composition of the present embodiment can be mentioned. The oxyalkylene group-containing poorly water-soluble drug obtained by introducing the divalent group B into the poorly water-soluble drug can be synthesized by various chemical reactions that can form a covalent bond between the two.

[0134] In the solubility improvement method of the present embodiment, by linking two types of poorly water-soluble compounds with the divalent group B, the solubility of the compound containing both can be improved. For example, by linking the first poorly water-soluble drug and the second poorly water-soluble drug with the divalent group B (the structure having an oxyalkylene group), an oxyalkylene group-containing poorly water-soluble drug with improved solubility can be synthesized. By using the ligand of the E3 ligase as the first poorly water-soluble drug and the site that binds to the target protein to be decomposed by the E3 ligase as the second poorly water-soluble drug, the solubility of the PROTAC molecule can be improved.

Examples

[0135] Hereinafter, the present invention will be described in detail by way of examples, but these are not intended to limit the scope of the present invention to the examples.

[0136] <PROTAC molecule> In the following experiments, the following PROTAC molecules were used. (±)-Thalidomide: manufactured by Sigma-Aldrich, product number: T144-100mg Lenalidomide: manufactured by TCI (Tokyo Chemical Industry), product number: L0332 Pomalidomide: manufactured by TCI, product number: P2074 VHL032: manufactured by Medchemexpress, product number: HY-120217 ARV-110: manufactured by Medchemexpress, product number: H-138641 ARV-825: Medchemexpress, product number: H-16954 CC220: Medchemexpress, product number: H-101291 MZ 1: Medchemexpress, product number: H-107425 ARCC-4: Medchemexpress, product number: H-130492

[0137] [ka]

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143] In the above chemical formula, "A" represents the target site of E3 ligase, "B" represents the divalent group B, and "C" represents the binding site with the target protein. Note that CC220 contains the divalent group B in the binding site with the target protein.

[0144] <Synthesis of hyaluronic acid derivatives> [Synthesis Example 1] As described in Examples 1 and 2 of International Publication No. 2010 / 053140, a hyaluronic acid derivative with cholesteryl groups introduced (weight average molecular weight: 10 kDa, cholesteryl group introduction rate: 30%) (hereinafter, sometimes referred to as "CHHA10k30%)" was synthesized.

[0145] [Synthesis Example 2] As described in Examples 1 and 2 of International Publication No. 2010 / 053140, a hyaluronic acid derivative with cholesteryl groups introduced (weight average molecular weight: 10 kDa, cholesteryl group introduction rate: 40%) (hereinafter, sometimes referred to as "CHHA10k40%)" was synthesized.

[0146] [Synthesis Example 3] As described in Examples 1 and 2 of International Publication No. 2010 / 053140, a hyaluronic acid derivative with cholesteryl groups introduced (weight average molecular weight: 35 kDa, cholesteryl group introduction rate: 19%) (hereinafter, sometimes referred to as "CHHA35k19%)) was synthesized.

[0147] [Synthesis Example 4] As described in Examples 1 and 2 of International Publication No. 2010 / 053140, a hyaluronic acid derivative with cholesteryl groups introduced (weight-average molecular weight of 10 kDa, cholesteryl group introduction rate of 45%) (hereinafter referred to as "CHHA10k45%") was synthesized.

[0148] [Example 1] A formulation using a hyaluronic acid derivative (10k40) was prepared. The following operations were carried out at room temperature (20°C). The freeze-dried hyaluronic acid derivative (10kJ 40%) obtained in Synthesis Example 2 was added to water for injection to the concentration listed in the "Raw Materials" column of Table 1, and stirred for 24 hours to dissolve, thereby preparing an aqueous solution of hyaluronic acid derivative. In a separate vial, powdered drug (API) ARV-110 was weighed out in the amount listed in the "Raw Materials" column of Table 1. Next, the hyaluronic acid derivative aqueous solution was added to the vial containing the powder, and the drug was complexed while stirring with a stirrer. The hyaluronic acid derivative aqueous solution was added until the drug residue was almost completely dissolved by visual inspection, and then the mixture was stirred for 12 hours to homogenize, preparing a hyaluronic acid derivative pharmaceutical composition (formulation). Finally, the mixture was filtered through a 0.22 μm sterile filtration filter (Pall, product number: 4612), and the drug concentration in the formulation was quantified by reverse-phase high-performance liquid chromatography (HPLC). The final formulation composition is shown in Table 1. In the table, "Loading API conc." in the "CHHA-API solution" column indicates the theoretical drug concentration in the composition before sterile filtration. Furthermore, "Loading API wt% vs. CHHA" is the ratio (%) of the drug amount (mass) to the hyaluronic acid amount (mass) in the drug-hyaluronic acid derivative complex in the composition before sterile filtration. In the table, "API conc." in the "Final formulation" column indicates the drug concentration in the final formulation as determined by reverse-phase HPLC.

[0149] [Example 2] to [Example 20], [Comparative Example 1] to [Comparative Example 15] Hyaluronic acid derivative pharmaceutical compositions were prepared in the same manner as in Example 1, except that the hyaluronic acid derivatives and drugs listed in the "Raw Materials" column of Table 1 or 2 were used. The final formulation composition is shown in the "CHHA-API Solution" column of Table 1 or 2.

[0150] [Table 1]

[0151] [Table 2]

[0152] [Test Example 1] The degree of solubilization improvement due to complexation with a hyaluronic acid derivative was determined for the preparations produced in Examples 1 to 20 and Comparative Examples 1 to 15. The degree of solubilization improvement was defined as the ratio of the maximum solubility of the drug alone in water for injection to the drug concentration in the preparation (maximum solubility of the drug-hyaluronic acid derivative complex) ([degree of solubilization improvement] = [drug concentration in the preparation (mg / mL)] / [maximum solubility of the drug alone in water for injection (mg / mL)]).

[0153] First, to calculate the degree of solubilization improvement, an experiment was conducted to calculate the maximum solubility of the drug alone in water for injection. The powder of each drug (API) listed in Table 3 was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 20 mg / mL. The API concentration in water for injection was then adjusted to 0.1 mg / mL. The mixture was stirred at room temperature for 12 hours to homogenize the formulation. Finally, the solution was filtered through a 0.22 μm sterile filter (Pall, product number 4612), and the drug concentration in the formulation was quantified by reverse-phase high-performance liquid chromatography (HPLC). The final drug solubility (maximum solubility) in water for injection is shown in Table 3.

[0154] [Table 3]

[0155] Next, for the formulations produced in Examples 1 to 20 and Comparative Examples 1 to 15, the degree of solubilization improvement was determined based on the drug concentration (mg / mL) in the formulation and the maximum solubility of the drug alone in water for injection listed in Table 3. The results are shown in Tables 4 and 5.

[0156] [Table 4]

[0157] [Table 5]

[0158] As shown in Comparative Examples 1 to 12 in Table 5, the CRBN ligands thalidomide, pomalidomide, and lenalimid had a solubilization improvement of 1 or less, and their solubility worsened when complexed with (A) a hyaluronic acid derivative. In contrast, as shown in Examples 1 to 8 and 13 to 16 in Table 4, ARV-110, ARV-825, and MZ-1, which are compounds in which the CRBN ligand and the target protein binding site are linked by a divalent group B, had a solubilization improvement of 2 or more, and their aqueous solubility was improved by complexing with (A) a hyaluronic acid derivative. As shown in Examples 9 to 12 in Table 4, CC220, which originally contains a divalent group B in the target protein binding site itself, also had a solubilization improvement of 2 or more, and its aqueous solubility was improved by complexing with (A) a hyaluronic acid derivative. Furthermore, as shown in Comparative Examples 13 to 15 in Table 5, the degree of solubilization improvement of the VHL ligand VHL032 was less than 3, whereas ARCC-4, in which the divalent group B was added to VHL032, had a degree of solubilization improvement of 20 or more, demonstrating a 10-fold or greater improvement in solubilization due to the addition of the divalent group B. In particular, ARV-825, MZ-1, and ARCC-4, in which the divalent group B contained an oxyalkylene group, had a degree of solubilization improvement of 10 or more, demonstrating a very high solubility improvement effect. [Industrial Applicability]

[0159] According to the present invention, a hyaluronic acid derivative pharmaceutical composition can be provided that has excellent water solubility for a compound having a site that targets E3 ligase, such as a PROTAC molecule.

Claims

1. (A) a hyaluronic acid derivative having a steryl group introduced therein; and (B) an active ingredient, the active ingredient (B) is a compound having a site that targets E3 ligase and a divalent group having a molecular weight of 70 or more and 300 or less; Hyaluronic acid derivative pharmaceutical composition.

2. The hyaluronic acid derivative pharmaceutical composition according to claim 1, wherein the divalent group contains an oxyalkylene group having 1 to 6 carbon atoms and 1 to 5 carbon atoms.

3. The hyaluronic acid derivative pharmaceutical composition according to claim 1, wherein the divalent group comprises two groups selected from the group consisting of aliphatic cyclic groups and aliphatic heterocyclic groups, or one group selected from the group consisting of aliphatic cyclic groups and aliphatic heterocyclic groups and one group selected from the group consisting of aryl groups and heteroaryl groups, linked by an alkylene group having 1 to 6 carbon atoms.

4. the active ingredient (B) is a compound having a site that targets the E3 ligase and a site that binds to a target protein to be degraded by the E3 ligase, the divalent group links the site that targets the E3 ligase to the site that binds to the target protein to be degraded by the E3 ligase, or the site that binds to the target protein to be degraded by the E3 ligase contains the divalent group. The hyaluronic acid derivative pharmaceutical composition according to any one of claims 1 to 3.

5. The hyaluronic acid derivative pharmaceutical composition according to claim 4, wherein the active ingredient (B) is a proteolysis-inducing chimeric protein compound.

6. The hyaluronic acid derivative pharmaceutical composition according to claim 5, wherein the E3 ligase targeting site is a VHL ligand or a CRBN ligand.

7. The hyaluronic acid derivative pharmaceutical composition according to claim 4, wherein the target protein is a protein selected from the group consisting of androgen receptor, estrogen receptor, BET family protein, IKAROS transcription factor family protein, and Bcl family protein.

8. The hyaluronic acid derivative pharmaceutical composition according to claim 5, wherein the molecular weight of the proteolysis-inducing chimeric protein compound is 500 or more and 5,000 or less.

9. The hyaluronic acid derivative pharmaceutical composition according to claim 5, wherein the solubility of the proteolysis-inducing chimeric protein compound in water is 1 mg / mL or less.

10. The hyaluronic acid derivative pharmaceutical composition according to claim 5, wherein the proteolysis-inducing chimeric protein compound is ARV-110, ARV-825, CC220, MZ-1, or ARCC-4.

11. The hyaluronic acid derivative pharmaceutical composition according to any one of claims 1 to 3, wherein the average molecular weight of the hyaluronic acid derivative (A) into which a steryl group has been introduced is 3,000 or more and 40,000 or less.

12. The hyaluronic acid derivative pharmaceutical composition according to any one of claims 1 to 3, wherein the steryl group introduction rate of the hyaluronic acid derivative (A) into which a steryl group has been introduced is 15 to 60%.

13. The hyaluronic acid derivative pharmaceutical composition according to any one of claims 1 to 3, wherein the (A) hyaluronic acid derivative having a steryl group introduced therein has one or more repeating units represented by the following general formula (I): 【Chemistry 1】 (In the formula, R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl, formyl and C １－６ alkylcarbonyl. Z represents a direct bond or a peptide linker consisting of any amino acid residues of 2 to 30. X １ is -NR ｂ -R, -NR ｂ -COO-R, -NR ｂ -CO-R, -NR ｂ -CO-NR ｃ -R, -COO-R, -O-COO-R, -SR, -CO-Y ａ -SR, -O-CO-Y ｂ -S-R, -NR ｂ -CO-Y ｂ It is a group selected from the group consisting of groups represented by -SR and -SSR. R ａ , R ｂ and R ｃ are each independently a hydrogen atom, C １－２０ Alkyl, Amino C ２－２０ Alkyl and hydroxy C ２－２０ R is a group selected from the group consisting of alkyl. ａ , R ｂ and R ｃ The alkyl portion of the formula is —O— and —NR ｆ - may be inserted with a group selected from the group consisting of: R ｆ is a hydrogen atom, C １－１２ Alkyl, Amino C ２－１２ Alkyl and hydroxy C ２－１２ R is a group selected from the group consisting of alkyl. ｆ The alkyl portion of the formula may have inserted therein a group selected from the group consisting of -O- and -NH-. R is a steryl group. Y is C ２－３０ Alkylene, or -(CH ２ CH ２ O) ｍ -CH ２ CH ２ Here, the alkylene of Y is —O—, —NR ｇ A group selected from the group consisting of - and -S-S- may be inserted. R ｇ is a hydrogen atom, C １－２０ Alkyl, Amino C ２－２０ Alkyl and hydroxy C ２－２０ R is a group selected from the group consisting of alkyl. ｇ The alkyl portion of the formula may have inserted therein a group selected from the group consisting of -O- and -NH-. Y ａ is C １－５ It is alkylene. Y ｂ is C ２－８ Alkylene or C ２－８ It is alkenylene. m is an integer of 1 or more and 100 or less.

14. The hyaluronic acid derivative pharmaceutical composition according to any one of claims 1 to 3, wherein the steryl group is a cholesteryl group.

15. A method for improving the water solubility of a poorly water-soluble drug, comprising: A method for complexing the poorly water-soluble drug with a hyaluronic acid derivative having a steryl group introduced therein, the poorly water-soluble drug being introduced with a structure having an oxyalkylene group with a molecular weight of 70 or more and 300 or less and having 1 to 5 carbon atoms.

16. The method according to claim 15, wherein the oxyalkylene group-containing poorly water-soluble drug is a compound in which a first poorly water-soluble drug and a second poorly water-soluble drug are linked together by a structure having the oxyalkylene group.

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