TW201737946A - Drug-conjugated block copolymer, block copolymer, and method for producing drug-conjugated block copolymer - Google Patents

Abstract

The present invention provides a polymer DDS which enables the controlled release of a drug having a carboxyl group. A drug-conjugated block copolymer according to the present invention is represented by the general formula: A-B. In the general formula, A represents a polyethylene glycol chain segment; and B represents a copolyamino acid chain segment containing a repeating unit represented by general formula (i) and/or (ii), wherein X in each of formulae (i) and (ii) represents a residue of the drug and the residue may have a linking group.

Description

Method for producing drug composite block copolymer, block copolymer and drug composite block copolymer

The present invention relates to a method for producing a drug-complexed block copolymer, a block copolymer, and a drug-complexed block copolymer.

As a technique for using a drug delivery system (DDS) having a polyethylene glycol segment and a block copolymer of a copolymerized amino acid segment containing an acidic amino acid residue, there are the following documents.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2009/142326

The conventional polymer DDS described in Patent Document 1 has a mechanism of bonding a drug having a hydroxyl group to an acidic amino acid residue bonded to a polyamino acid segment via an ester bond using the hydroxyl group. The carrier is carried out under the action of a hydrolysis reaction accompanied by a structural change of the acidic amino acid residue. In the technical field of the conventional polymer DDS, the use of such a drug release mechanism is limited to the premise of the combination of an acidic amino acid residue and a drug having a hydroxyl group.

The main object of the present invention is to provide a polymer DDS which makes it possible to control the release of a drug having a carboxyl group.

According to the present invention, there is provided a drug-complexed block copolymer represented by the formula: A-B. A represents a polyethylene glycol segment, and B represents a copolymerized amino acid segment comprising a repeating unit represented by the following formula (i) and/or a repeating unit represented by the following formula (ii), In the general formula (i) and the following general formula (ii), X represents a residue of a drug which can have a linking group.

According to another aspect of the present invention, a block copolymer represented by the following formula (II) is provided.

[Chemical 3]

In the above formula, R ¹ represents a hydrogen atom, an unsubstituted or substituted alkyl group having a linear or branched carbon number of 1 to 12, or a group having a target bonding site; and R ² represents a hydrophobic group, R ³ represents a hydrogen atom, a saturated or unsaturated unsubstituted or substituted aliphatic or carbonyl group having a linear or branched carbon number of 1 to 30, or an unsubstituted or substituted carbon number of 1 to 12. Substituted linear or branched alkyl, L represents a linking group, m is an integer from 30 to 20,000, x is an integer from 5 to 100, a is an integer from 0 to 100, and b is an integer from 0 to 100, c The integer is from 0 to 100, d is an integer from 0 to 100, and the sum of a and c is from 1 to 200, and the bonding order of each of the above-mentioned copolymerized amino acid segments is arbitrary.

According to still another aspect of the present invention, there is provided a process for producing a drug-complexed block copolymer represented by the following formula (I).

[Chemical 4]

The above production method includes the steps of: making all or a part of the hydroxyl group of the side chain of the copolymerized amino acid segment of the block copolymer represented by the above formula (II), and a drug having a carboxyl group and having a linking group. The carboxyl group reacts to form an ester bond.

According to the present invention, there is provided a drug-complexed block copolymer which enables release control of a drug having a carboxyl group.

[1. Drug composite block copolymer]

The drug-complexed block copolymer of one embodiment of the present invention will be described below. The above drug-complexed block copolymerization system is represented by the general formula: A-B. A represents a polyethylene glycol segment. B represents a copolymerized amino acid segment comprising a repeating unit represented by the following formula (i) and/or a repeating unit represented by the following formula (ii). In the following general formula (i) and the following general formula (ii), X represents a residue of a drug which can have a linking group.

[Chemical 5]

The molecular weight of the polyethylene glycol segment is, for example, 500 or more, and may be 2,000 or more, and is, for example, 50,000 or less, and further preferably 20,000 or less.

The above-mentioned copolymerized amino acid segment is further typically represented by an amino acid residue having a hydrophobic group in the side chain. As the above amino acid residue, any suitable amino acid residue can be employed. The amino acid residue is preferably a glutamic acid residue having a hydrophobic group introduced into the side chain. As the above hydrophobic group, any suitable hydrophobic group can be employed. Examples of the hydrophobic group include a hydrophobic organic group. Examples of the hydrophobic organic group include a C ₄ to C ₁₆ alkyl group having a linear, branched or cyclic structure, a C ₆ to C ₂₀ aryl group, and a C ₇ to C ₂₀ aralkyl group. Or sterol residues. Preferred examples of the aryl group of C ₆ to C _{20 and} the aralkyl group of C ₇ to C ₂₀ include a phenyl group, a naphthyl group, a tolyl group, a xylyl group, a benzyl group, and a phenethyl group, and further preferably A benzyl group is mentioned. Further, the sterol from which the sterol residue is derived is preferably cholesterol, dihydrocholesterol, and dihydroxycholesterol, and more preferably cholesterol.

The above-mentioned copolymerized amino acid segment is further included in the side chain An amino acid residue having a hydrophilic group. As the above amino acid residue, any suitable amino acid residue can be employed. The amino acid residue is preferably an aspartic acid residue obtained by arbitrarily converting a carboxyl group of a side chain into another hydrophilic group. As the hydrophilic group, any suitable hydrophilic group can be employed. Examples of the hydrophilic group include a hydroxyl group.

The above drugs are compounds having a carboxyl group. For example, Ciprofloxacin, Cefepime, NMK-36, Alprostadil, Doripenem, Levofloxacin, Pazufloxacin, BILN-2061, Cefotiam, Talaporfin, Ceftriaxone, Tosufloxacin, Flomoxef, Prulifloxacin, ML -04, Imipenem, Enoxacin, PD-123177, Fenofibric Acid, Epristeride, Ofloxacin, Ina Enalapril, YY-984, cholic acid, valsartan, Ozagrel, Pazufloxacin, Ceftazidime, Erdosteine, thyroxine (Thyroxine), VX-809, Bezafibrate, Tazobactam, Tirofiban, Lubiprostone, Febuxostat, Aga Arbatroban, Eprosartan, Lomefloxacin, Peramivir, Remy Ramipril, Liothyronine, Methotrexate, Enoxacin, Flurbiprofen, Gatifloxacin, Eprilet (Epristeride), Candesartan, Fenofibric Acid, Alvogen, Etodolac, Benazepril, CV11974, CV2961, CV2973, Aceh Azilsartan, acetaminophen, Ampicillin, Ibuprofen, Indometacin, Captopril, Diclofenac, Venlafaxine, Nateglinide, Nu-lotan, Pravastatin, Penicillin, Mitiglinide, Methicillin, Lipitor, Repaglinide ), Levocetirizine, Levofloxacin, Loxoprofen, Oxacillin, Ro64-0802, Trifarotene, Bendamustine, valproic acid ( Valpronic Acid), Methotrexate, GSK-2636771, (R)-folitixorin, Melphalan, Aminolevulinic Acid, Rigosertib, Technetium Tc 99m Trofolastat, MLN9708 , GPC-3298306, S-588410, Minerval, CPI-613, CMS-024-02, angiotensin (1-7) (Angiotensin-(1-7)), 177Lu-DOTATATE, MLN8237, CMS024, DCDS4501A, 1 -Methyl-D-tryptophan (Indoximod), NMK-36, 18F-ML-10, Mipsagargin, MK-8109, Elp Amotide, Nelipipimut-S, CBP-501, Tamibarotene, Levothyroxine, Bexarotene, A-melamine stimulating hormone (Afamelanotide), GlutaDON, Technetium (99mTc) Etarfolatide, Luminespib, Salirasib, A-6, Vosaroxin, TSU-68, Peretinoin, Pralatrexate, Leucovorin, PCI-27483, Emepepimut-S, Itriglumide, ML- 04, Eltrombopag, Febuxostat, Ubenimex, Tretinoin, Indium111 Pentetreotide, TLK286, SPI-1620, Pemetrex Pemetrexed, Raltitrexed, E7974 (hemiasterlin derivatives), and RQ-00000008.

The drug having a carboxyl group may be in a state in which a linking group is disposed between the active region portion and the carboxyl group. As described above, the compound in a state in which a linking group is disposed between the active region portion of the drug and the carboxyl group is also used as the drug having the carboxyl group. Examples of the linking group include a divalent linking group having a carbon number of 0 to 5 which may have a guanamine bond, an ester bond, an ether bond, and/or a hydrazone bond.

The above drug-complexed block copolymer is preferably represented by the following formula (I).

In the above formula, R ¹ represents a hydrogen atom, an unsubstituted or substituted alkyl group having a linear or branched carbon number of 1 to 12, or a group having a target bonding site. R ² represents a hydrophobic group. R ³ represents a hydrogen atom, a saturated or unsaturated unsubstituted or substituted aliphatic or carbonyl group having a straight or branched carbon number of 1 to 30, or an unsubstituted or substituted carbon number of 1 to 12 or A substituted linear or branched alkyl group. L represents a linking group. m is an integer from 30 to 20,000. x is an integer from 5 to 100. a is an integer from 0 to 100. b is an integer from 0 to 100. c is an integer from 0 to 100. d is an integer from 0 to 100. The sum of a and c is 1 to 200. The bonding order of each of the above-mentioned repeating units in the above-mentioned copolymerized amino acid segment is arbitrary.

In the present specification, the target binding site refers to a site having a biological recognition function that is specifically bonded to a substance derived from a living body and a virus to form a biological bond pair with the substance. The group having a target bonding site is, for example, a low molecular compound, a sugar chain, a peptide, an antibody, a fragment thereof, or the like, and may contain a compound capable of forming a biological bond pair with a substance derived from a living body and a virus as at least a part of its structure. It is composed of states.

As the above-mentioned linking group, any suitable linking group can be employed. The above-mentioned linking group may, for example, be selected from the group consisting of -NH-, -O-, -OZ-NH-, -CO-, -CH ₂ -, -OZSZ-, and -OCO-Z-NH- (here, Z independent) The ground is a linking group in the group consisting of C ₁ -C ₆ alkylene groups.

In the above formula (I), m is an integer of 30 to 20,000 as described above. m may be, for example, an integer of 50 or more, an integer of 100 or more, or an integer of 200 or more, and may be, for example, an integer of 5,000 or less, an integer of 500 or less, or an integer of 300 or less.

In the above formula (I), x is an integer of 5 to 100 as described above. x may be, for example, an integer of 10 or more, or an integer of 15 or more, and may be, for example, an integer of 60 or less, an integer of 40 or less, or an integer of 25 or less.

In the above formula (I), a is an integer of 0 to 100 as described above. a may be, for example, an integer of 1 or more, or an integer of 5 or more, and may be, for example, an integer of 60 or less, and further an integer of 40 or less.

In the above formula (I), b is an integer of 0 to 100 as described above. b may be, for example, an integer of 1 or more, or an integer of 5 or more, and may be, for example, an integer of 60 or less, and further an integer of 40 or less.

In the above formula (I), c is an integer of 0 to 100 as described above. c can be an example For example, an integer of 1 or more and an integer of 5 or more may be an integer of 60 or less, and an integer of 40 or less.

In the above formula (I), d is an integer of 0 to 100 as described above. d may be, for example, an integer of 1 or more, or an integer of 5 or more, and may be, for example, an integer of 60 or less, and further an integer of 40 or less.

In the above formula (I), the sum of a and c is an integer of from 1 to 200 as described above. The sum of a and c may be, for example, an integer of 2 or more, an integer of 3 or more, an integer of 4 or more, an integer of 5 or more, or an integer of 6 or more, and may be, for example, an integer of 40 or less, an integer of 20 or less, or 10 The following integers, and further integers of 8 or less.

In the above formula (I), the sum of x and a, b, c and d may be, for example, 10 or more, 20 or more, or more preferably 30 or more, and may be, for example, 200 or less, 100 or less, or further 50 or less.

In the above formula (I), x: (a + b + c + d) is, for example, 90:10 to 10:90, and further, for example, 80:20 to 20:80.

In the above formula (I), x:(b+d) is, for example, 20:80 to 80:20, and further, for example, 25:75 to 75:25, and further, for example, 30:70 to 70:30.

In the above formula (I), the ratio (%) of (a+c) to (x+a+b+c+d) may be, for example, 2% or more, further 7% or more, and may be, for example, 50% or less. And further 35% or less.

In the above formula (I), (a+c):(b+d) is, for example, 90:10 to 30:70, and is, for example, 80:20 to 30:70.

In the above formula (I), x/(a+c) may be, for example, 0.5 or more and further 1 or more, and may be, for example, 15 or less and further 10 or less.

[2. Block copolymer]

The block copolymer of one embodiment of the present invention will be described below. The above block copolymerization system is represented by the following formula (II).

In the above formula (II), R ¹ , R ² , R ³ , L, m, x, a, b, c, and d are as described in the above formula (I). The bonding order of each of the above-mentioned repeating units in the above-mentioned copolymerized amino acid segment is arbitrary.

In one embodiment, the block copolymer represented by the formula (III) represented by the above formula (II) is a block copolymer represented by the formula (III).

In the above formula (III), R ¹ , R ² , R ³ , L, m, and x are as described in the above formula (I), and e and f are each independently an integer of 0 to 200, and e+f It is an integer from 1 to 200. Further, the bonding order of each of the repeating units in the above-mentioned copolymerized amino acid segment is arbitrary.

In the above formula (III), e and f are each independently, and may be, for example, an integer of 0 or more, an integer of 2 or more, or an integer of 10 or more, and may be, for example, an integer of 200 or less, and an integer of 120 or less. Further, an integer of 80 or less.

In the above formula (III), e+f may be, for example, an integer of 5 or more, and further an integer of 10 or more, and may be, for example, an integer of 100 or less, and an integer of 60 or less.

In the above formula (III), (x+e+f) may be, for example, 10 or more and further 20 or more, and may be, for example, 200 or less and further 100 or less.

In the above formula (III), x:(e+f) may be, for example, 90:10 to 10:90, and may be, for example, 80:20 to 20:80.

[3. Method for producing drug composite block copolymer]

A method for producing a drug-complexed block copolymer according to an embodiment of the present invention will be described below. The above production method is a method for producing a drug-complexed block copolymer represented by the above formula (I).

Specific examples of the method for producing the drug-complexed block copolymer will be described below.

The above production method includes the steps of: making all or a part of the hydroxyl group of the side chain of the copolymerized amino acid segment of the block copolymer represented by the above formula (II) and having a carboxyl group and having a linking group. The carboxyl group of the drug reacts to form an ester bond.

The above production method may further have the step of preparing polyethylene glycol-co-glutamic acid R ² ester-polyaspartic acid (PEG-PR ² LG-pAsp). In the above-mentioned copolymerized amino acid segment, a glutamic acid residue having an ester-bonded R ² and an aspartic acid residue are arbitrarily disposed in a side chain.

The above production method may further comprise the step of reducing a carboxyl group of the aspartic acid side chain of PEG-PR ² LG-pAsp to form a hydroxyl group. As a result, it is possible to obtain a polyethylene glycol-co-amino acid, and a copolymer of a glutamic acid residue having an ester-bonded R ² and a reducing aspartic acid residue in an arbitrary side chain. (PEG-PR ² LG-pAsp (red)) (that is, a block copolymer represented by the formula (II)).

(ester bond forming step)

Any suitable method can be employed as a method of reacting the hydroxyl group with the carboxyl group of the above-mentioned drug having a carboxyl group to form an ester bond.

(PEG-PR ² LG-pAsp preparation step)

As an example of a method of preparing PEG-PR ² LG-pAsp, a method of polymerizing a polymer having a polyethylene glycol (PEG) chain and having a copolymerized glutamic acid R ² ester by any suitable method may be mentioned. The polymer of the towline (PR ² LG-pAsp) was coupled.

As another example of the method of preparing PEG-PR ² LG-pAsp, a method in which aspartic acid anhydride (Asp-) is used as a starting agent with a single terminal protected and an amine group having an amine group at the other end is used as a starting agent. NCA) and N-carboxy-γ-R ² -L-glutamic acid anhydride (R ² LG-NCA) are added so as to have a desired degree of polymerization (unit number of amino acids), and these are allowed to react. As the above initiator, any suitable initiator can be employed. As the above initiator, for example, MeO-PEG-CH ₂ CH ₂ CH ₂ -NH _{2 can} be mentioned. The above reaction is preferably carried out in a dehydrated organic solvent.

(PEG-PR ² LG-pAsp reduction step)

As a method of reducing the carboxyl group of the aspartic acid side chain to form a hydroxyl group, any suitable method can be employed.

[4. Polymeric cell medicinal composition]

A polymer microcapsule pharmaceutical composition comprising a drug-complexed block copolymer (hereinafter sometimes referred to as a block copolymer unit α) according to an embodiment of the present invention will be described below. The above polymer microcell medicinal composition may further comprise a block copolymer unit β having a polyethylene glycol segment and a polyamino acid segment bonded to a target bonding site. It is not a block copolymer unit alpha. The polymer microcell medicinal composition may further comprise a block copolymer unit γ, the block copolymer unit γ containing neither a target bonding site nor a drug, but having a polyethylene glycol segment and a poly Amino acid segment.

In the case of the above-mentioned polymer microcapsule medical composition, in the case where the block copolymer unit α and the coexistence, the β and γ are radially arranged in a state in which the polyethylene glycol segments are oriented outward. In the present specification, the block copolymer is radially arranged as long as it is in a state in which the polyethylene glycol segment faces outward and the segment on the opposite side to the polyethylene glycol segment (copolymerization) The amino acid segment) agglomerates toward the inside.

The polydispersity index (PDI: Polydispersity Index) of the above polymer microcell medicinal composition may take any suitable value. The polydispersity index may be, for example, 0.01 or more and further 0.02 or more, and may be, for example, 0.8 or less and further 0.5 or less.

The content of the block copolymer unit α in the above-mentioned polymer microcell medicinal composition may be any suitable value. The content is, for example, 20% by weight or more, and is, for example, 30% by weight or more. By the above content being a predetermined value or more, It is easier to carry a sufficient amount of the drug in the polymer microcell medicinal composition. On the other hand, the content is, for example, 90% by weight or less, and is, for example, 80% by weight or less, and for example, 70% by weight or less.

The block copolymer may further contain two or more kinds of β and γ in the case where the above-mentioned block copolymer unit α is contained.

The block copolymer unit units β and γ of the polyamino acid segment are preferably each an amino acid residue having a hydrophobic group in the side chain. As the above amino acid residue, any suitable amino acid residue can be employed. Examples of the amino acid residue include a glutamic acid residue and an aspartic acid residue in which a hydrophobic group is introduced into a side chain. As the above hydrophobic group, any suitable hydrophobic group can be employed. Examples of the hydrophobic group include a hydrophobic group described in the drug-complexed block copolymer.

The polyamino acid segment of the block copolymer unit γ is preferably an amino acid residue having a hydrophilic group in the side chain. As the above amino acid residue, any suitable amino acid residue can be employed. Examples of the amino acid residue include a glutamic acid residue and an aspartic acid residue. As the hydrophilic group, any suitable hydrophilic group can be employed. As the hydrophilic group, for example, a carboxyl group can be mentioned.

[Examples]

Hereinafter, the present invention will be specifically described by way of examples, but the invention is not limited to the examples. The test and evaluation methods in the examples are as follows. Further, as long as it is not clearly stated, "parts" and "%" in the examples are based on weight.

[Test Example 1]

A polymer micelle carrying ibuprofen as a drug was formed in the following manner.

(Preparation of drug-complexed block copolymer)

The drug-complexed block copolymer represented by the above formula (I) was prepared in the following manner. Reduced aspartic acid residue of polyethylene glycol-co-glutamic acid glutamic acid-polyreduced aspartic acid (PEG-PBLG-pAsp(red)) which is acetylated at the single end of the copolymerized amino acid The hydroxyl group of the side chain of the group reacts with the carboxyl group of ibuprofen to form an ester bond. As a result, the drug-complexed block copolymer represented by the above formula (I) was obtained. With respect to the obtained drug-complexed block copolymer (indicated as "PEG-PBLG-pAsp(red)-IB" in Table 1), the number of ibuprofen residues was measured by NMR, and the measured results are shown in the table. 1. In Table 1, "AA" indicates the average value of the number of amino acid residues of the above-mentioned drug-complexed block copolymer, and "PEG MW" indicates the average molecular weight (Mw) of PEG (PEG having an average molecular weight (Mw) of 10,000). The degree of polymerization is calculated to be about 226 to 227). "Bn:OH ratio" means the average of the number of glutamic acid ester residues of the side chain in the block copolymer before compounding: (the average number of hydroxyl groups of the reduced aspartic acid residue) value). The "IB number" indicates the average value of the number of ibuprofen residues measured by NMR in the drug-complexed block copolymer.

(Preparation of micelles)

Methanol or acetone is added to the above-mentioned drug-complexed block copolymer to dissolve. Thereafter, the solvent was distilled off by a rotary evaporator (manufactured by Buchi, Rotavapor R-205, Vac ^(R) V-513) to form a film of the polymer, which was further dried overnight. After the film was dispersed by adding 100 mM PBS (pH 7.4), the polymer micelles were obtained by high-pressure dispersion treatment using a NanoVater (manufactured by Yoshida Machinery Co., Ltd., NM2-L200). The microcell component includes the polymer micelles obtained by radially arranging the drug-complexed block copolymers. For the obtained polymer micelles (indicated as "pAsp (red) micelles in Table 2) and the above-mentioned drug-complexed block copolymer, the ibuprofen content was determined and the measured results are shown in Table 2. . In Table 2, "IB _NMR " indicates the ibuprofen content (%) in the drug-complexed block copolymer measured by NMR. Further, "IB _HPLC " means the ibuprofen content (%) in the polymer micelles as measured by HPLC.

[Test Example 2]

Substituting PEG-PBLG-pAsp(red) with acetylated polyethylene glycol-co-benzyl glutamate-poly-reduced glutamic acid (PEG-PBLG-pGlu(red)) with a single terminal of a copolyamino acid Except for this, a drug-complexed block copolymer was prepared in the same manner as in Test Example 1. For the obtained drug-complexed block copolymer (indicated as "PEG-PBLG-pGlu(red)-IB" in Table 1), the number of ibuprofen residues was determined by NMR and the measured results were shown in Table 1. Further, the polymer micelles were obtained by the same method as in Test Example 1 using the above-mentioned drug composite block copolymer. For the obtained polymer micelles (indicated as "pGlu (red) micelles in Table 2) and the above-mentioned drug-complexed block copolymer, the ibuprofen content was determined and the measured results are shown in Table 2. .

(ibuprofen release test)

The microcapsules of Test Examples 1 and 2 were added to PBS in a hot water bath at 37 ° C so that the ibuprofen concentration was 1 μg/mL, and the mixture was slowly shaken. One portion of the PBS was recovered after 24 hours, and the concentration of ibuprofen released from the micelles into PBS was measured. Count The ratio (%) of the amount of ibuprofen released relative to the total amount of ibuprofen. The results are shown in Table 2 as "drug release rate".

[Test Example 3]

A polymer micelle in which E7974, which is a Hammetrine derivative represented by the following formula (iii), was used as a drug was formed as follows.

(Preparation of drug-complexed block copolymer)

A drug-complexed block copolymer was prepared in the same manner as in Test Example 1, except that E7974 was used as the drug. With respect to the obtained drug-complexed block copolymer (indicated as "PEG-PBLG-pAsp(red)-E7974" in Table 3), the number of E7974 residues was measured and the measured results are shown in Table 3. In Table 3, "AA", "PEG MW", and "Bn:OH ratio" have the same meanings as in Table 1. The "E7974 number" indicates the average value of the number of E7974 residues in the drug-complexed block copolymer measured by HPLC after hydrolysis.

(Preparation of micelles)

The polymer micelles were obtained in the same manner as in Test Example 1 using the above drug-combined block copolymer. The microcell component contains the polymer micelles obtained by radially arranging the above-mentioned drug-complexed block copolymer. For the obtained polymer micelles (indicated as "pAsp (red) micelles in Table 4), the E7974 content was measured and the measured results are shown in Table 4. In Table 4, "E7974 content (HPLC)" means the E7974 content (%) in the polymer micelles as measured by HPLC.

[Test Example 4]

Substituting PEG-PBLG-pAsp(red) with acetylated polyethylene glycol-co-benzyl glutamate-poly-reduced glutamic acid (PEG-PBLG-pGlu(red)) with a single terminal of a copolyamino acid A drug-complexed block copolymer was prepared in the same manner as in Test Example 3 except for the above. The number of E7974 residues was determined for the obtained drug-complexed block copolymer (indicated as "PEG-PBLG-pGlu(red)-E7974" in Table 3), and the results obtained are shown in Table 3. Further, polymer micelles were obtained in the same manner as in Test Example 1 using the above-mentioned drug-complexed block copolymer. The E7974 content was determined for the obtained polymer micelles (indicated as "pGlu(red) micelles in Table 4) and the measured results are shown in Table 4.

(E7974 release test)

The concentration of E7974 in PBS which was subjected to a hot water bath at 37 ° C was 1 μg/mL. The microcapsule preparations of Test Examples 3 and 4 were added in such a manner as to slowly oscillate. One portion of the PBS was recovered after 24 hours, and the concentration of E7974 released from the micelles into PBS was measured. The ratio (%) of the released amount of E7974 to the total amount of E7974 was calculated. The results are shown in Table 4 as "drug release rate".

According to Table 2 and Table 4, in the use of a polyethylene glycol-co-amino acid copolymer as a drug-complexed block copolymer polymer microparticle pharmaceutical composition, by using the above-mentioned copolymerized amino acid segment The reduced aspartic acid side chain is bonded with a polyethylene glycol-copolyamino acid copolymer of a drug, and release control of a drug having a carboxyl group is possible.

(industrial availability)

The present invention can be preferably used in the fields of pharmaceutical preparations such as anticancer agents.

Claims (20)

A drug-complexed block copolymer represented by the formula: AB, wherein A represents a polyethylene glycol segment, and B represents a repeating unit represented by the following formula (i), and/ Or a copolymerized amino acid segment of a repeating unit represented by the following formula (ii): in the following formula (i) and the following formula (ii), X represents a residue of a drug which may have a linking group , The drug-complexed block copolymer of claim 1, wherein the copolymerized amino acid segment further contains a glutamic acid residue having a hydrophobic group introduced into the side chain as a repeating unit. The drug-combined block copolymer of claim 1 or 2, which is represented by the following formula (I), In the above formula, R ¹ represents a hydrogen atom, an unsubstituted or substituted alkyl group having a linear or branched carbon number of 1 to 12, or a group having a target bonding site, and R ² represents a hydrophobic group, R ³ represents a hydrogen atom, a saturated or unsaturated unsubstituted or substituted aliphatic or carbonyl group having a linear or branched carbon number of 1 to 30, or an unsubstituted or substituted carbon number of 1 to 12. Substituted linear or branched alkyl, L represents a linking group, m is an integer from 30 to 20,000, x is an integer from 5 to 100, a is an integer from 0 to 100, and b is an integer from 0 to 100, c The integer is from 0 to 100, d is an integer from 0 to 100, and the sum of a and c is from 1 to 200, and the bonding order of each of the above-mentioned copolymerized amino acid segments is arbitrary. The drug-combined block copolymer of claim 3, wherein in the above formula (I), the sum of x and a and b and c and d is 10 to 200. The drug-combined block copolymer of claim 3 or 4, wherein, in the above formula (I), the sum of a and c is from 3 to 40. The drug-combined block copolymer of claim 5, wherein, in the above formula (I), the sum of a and c is 4 to 20. The drug-complexed block copolymer according to any one of claims 3 to 6, wherein in the above formula (I), x is from 5 to 60. The drug-combined block copolymer of claim 7, wherein x in the above formula (I) is from 10 to 60. The drug-complexed block copolymer according to any one of claims 3 to 8, wherein, in the above formula (I), x:(b+d) is 20:80 to 80:20. The drug-complexed block copolymer of any one of claims 1 to 9, wherein X is a residue of a drug having a carboxyl group. The drug-combined block copolymer of claim 10, wherein X is a residue of a drug in a state in which a linking group is disposed between a living region portion and a carboxyl group. The drug-combined block copolymer of claim 11, wherein the linking group is a divalent linking group having a carbon number of 0 to 5 which may further contain a guanamine bond, an ester bond, an ether bond, and/or a hydrazone bond. The drug-complexed block copolymer of any one of claims 1 to 12, wherein X is a residue of a Hamesterlin derivative represented by the following formula (iii), [Chem. 4] The drug-complexed block copolymer of claim 3, wherein X is a residue of a Hammetrine derivative represented by the following formula (iii), R ¹ is a hydrogen atom, an unsubstituted or substituted alkyl group having a linear or branched carbon number of 1 to 12, or a group having a target bonding site, and R ² is a linear chain of C ₄ to C ₁₆ a branched or cyclic alkyl group, a C ₆ -C ₂₀ aryl group, and a C ₇ -C ₂₀ aralkyl or sterol residue, and R ³ is a hydrogen atom, a saturated or unsaturated unsubstituted Or a substituted straight or branched aliphatic carbonyl or arylcarbonyl group having 1 to 30 carbon atoms, or an unsubstituted or substituted straight or branched alkyl group having 1 to 12 carbon atoms, L It is selected from -NH-, -O-, -OZ-NH-, -CO-, -CH ₂ -, -OZSZ-, and -OCO-Z-NH- (here, Z is independently C ₁ ~ C ₆ The linking group in the group consisting of alkyl groups, m is an integer from 50 to 5000, x is an integer from 5 to 100, the sum of a and c is 2 to 40, and the sum of x and a and b and c and d is 10~200. The drug-complexed block copolymer of claim 14, wherein X is a residue of a Hammetrine derivative represented by the above formula (iii), and R ¹ is a hydrogen atom, an unsubstituted or substituted carbon number a linear or branched alkyl group of 1 to 12 or a group having a target bonding site, and R ² is a C ₄ -C ₁₆ alkyl group having a linear, branched or cyclic structure, C ₆ -C An aryl group of ₂₀ , and a C ₇ -C ₂₀ aralkyl or sterol residue, R ³ being a hydrogen atom, a saturated or unsaturated unsubstituted or substituted straight or branched carbon number of 1 to 30 An aliphatic carbonyl or arylcarbonyl group, or an unsubstituted or substituted straight or branched alkyl group having 1 to 12 carbon atoms, L being selected from the group consisting of -NH-, -O-, -OZ-NH a linking group in the group consisting of -, -CO-, -CH ₂ -, -OZSZ-, and -OCO-Z-NH- (wherein Z is independently a C ₁ -C ₆ alkylene group), m is 100 An integer of ~500, x is an integer from 10 to 60, the sum of a and c is 4 to 20, and the sum of x and a and b and c and d is 20 to 100. The drug-complexed block copolymer of claim 14, wherein X is a residue of the Hammetrine derivative represented by the above formula (iii), R ¹ is a methyl group, R ² is a benzyl group, and R ³ is Ethyl group, L is -NH-, m is 200~300, x is 15~25, the sum of a and c is 5~10, the sum of x and a and b and c and d is 30~50. The drug-complexed block copolymer of claim 14, wherein X is a residue of the Hammetrine derivative represented by the above formula (iii), R ¹ is a methyl group, R ² is a benzyl group, and R ³ is Ethyl group, L is -NH-, m is 226, x is 20, the sum of a and c is 6-8, and the sum of x and a and b and c and d is 40. A block copolymer represented by the following formula (II), In the above formula, R ¹ represents a hydrogen atom, an unsubstituted or substituted alkyl group having a linear or branched carbon number of 1 to 12, or a group having a target bonding site, and R ² represents a hydrophobic group, R ³ represents a hydrogen atom, a saturated or unsaturated unsubstituted or substituted aliphatic or carbonyl group having a linear or branched carbon number of 1 to 30, or an unsubstituted or substituted carbon number of 1 to 12. Substituted linear or branched alkyl, L represents a linking group, m is an integer from 30 to 20,000, x is an integer from 5 to 100, a is an integer from 0 to 100, and b is an integer from 0 to 100, c The integer is from 0 to 100, d is an integer from 0 to 100, and the sum of a and c is from 1 to 200, and the bonding order of each of the above-mentioned copolymerized amino acid segments is arbitrary. A method for producing a drug-complexed block copolymer, which is the method for producing a drug-complexed block copolymer represented by the above formula (I), which comprises the following steps: All or a part of the hydroxyl group of the side chain of the copolymerized amino acid segment of the block copolymer represented by the formula (II) is reacted with the carboxyl group of the drug having a carboxyl group and having a linking group to form an ester bond. A polymer microcell medicinal composition comprising the drug-complexed block copolymer of any one of claims 1 to 17.