JPWO2020209379A1 - Pharmaceutical composition for administration to pregnant or potentially pregnant women - Google Patents

Abstract

The challenge is to develop a drug that can be used during pregnancy. It has been found that in particles having a hydrophilic polymer to which a therapeutic agent is bound or coordinated, the particle size of the particles can be controlled by controlling the particle size of the particles by the hydrophilic polymer, and the particle size can be changed. The problem is solved by particles having a diameter of 10 to 100 nm when measured by a dynamic light scattering method.

Description

The present invention relates to pharmaceutical compositions for administration to pregnant or potentially pregnant women.

Dosing to pregnant women is avoided as much as possible to avoid effects on the foetation. Effects on the fetal include teratogenicity, miscarriage, premature birth and fetal stunting. There are only a limited number of drugs that have been established to be safe, and it is necessary to discontinue medication when pregnancy is known. Pregnant women may also suffer from excessive labor due to the discovery of pregnancy during dosing. On the other hand, discontinuation of medication often has an adverse effect on pregnant women, and development of a drug that can be used even during pregnancy is desired. Cancer is one of the problematic diseases during pregnancy. Approximately 200,000 pregnant women worldwide suffer from cancer, of which breast cancer has been reported to be associated with exposure to endogenous estrogen and progesterone and develops with pregnancy. There is also. The risk of breast cancer increases with age, but the number of cases of breast cancer in pregnant women increases with increasing age of pregnancy. Generally, for breast cancer, anticancer agents, hormone therapy, antibody therapeutic agents, radiation therapy, surgery, etc. are performed, but the anticancer agents that can be used for pregnant women are limited.

Inflammation during pregnancy, especially bacterial inflammation, is known to increase the risk of preterm birth and non-steroidal anti-inflammatory drugs such as indomethacin can be used therapeutically. On the other hand, it has been reported that non-steroidal anti-inflammatory drugs such as indomethacin affect the foetation and cause renal failure and gastrointestinal failure, and sufficient caution is required in their use.

Preeclampsia is known as a disease that occurs frequently in pregnant women, and occurs in about 1 in 20 people. Preeclampsia impairs renal and hepatic function, is dangerous to the mother, and can also cause fetal growth restriction. Antihypertensive agents such as hydralazine, methyldopa, labetalol, and nifedipine are commonly used to treat preeclampsia. Recent studies have reported that statins are useful for the treatment and / or prevention of preeclampsia (Non-Patent Document 1: Plos One (2010) vol. 5, Issue 10, e13663). The use of statins in pregnant women is contraindicated. In addition, some psychiatric drugs administered for the treatment of psychiatric disorders may cause teratogenicity or neonatal maladaptation syndrome, and the medication may be discontinued.

International Publication No. 96/32343 International Publication No. 96/33233 International Publication No. 97/06202

A. Ahmed Plos One (2010) vol. 5, Issue 10, e13663 H. Cabral et. Al., Nat. Nanotech. 6 (2011) 815-823 K. Shintaku et. Al., Drug Metab. Dispos. 37 (2009) 962, JR Huston et. Al., Clin. Pharmacol. Ther. 90 (2011) 6 M. Nagai et. Al., Drug Metab. Dispos. 41 (2013) 2124 M. Yokoyama et. Al., Makromol. Chem. 190 (1989) 2041-2054 A. Harada and K. Kataoka, Macromolecules 28 (1995) 5294-5299

The purpose is to develop a drug that can be used during pregnancy.

The present inventors conducted a study focusing on the placental permeability of a drug for the purpose of developing a drug that can be used during pregnancy. We have found that placental permeability can be controlled by controlling the size with a hydrophilic polymer, and have reached the present invention. Therefore, the present invention relates to the following:

（式中、
Ｒ^1a及びＲ^1bは、水素原子、水酸基又は未置換もしくは置換された直鎖もしくは分枝のＣ_1-12アルキル基又はＣ_1-12アルコキシ基を表し、
Ｌ¹は−（ＣＨ₂）_b−ＮＨ−を表し、ｂは１〜５の整数であり、
Ｌ²は−（ＣＨ₂）_c−ＣＯ−を表し、ｃは１〜５の整数であり、
Ｒ^2a、及びＲ^2ｃは、出現ごとに独立して、存在しないか、又はメチレン基を表し、
Ｒ^2b及びＲ^2dは、カルボキシ基又は任意のアミノ酸側鎖を表し、
Ｒ³は、水素原子、保護基、疎水性基又は重合性基を表し、
Ｒ⁴は、水酸基、オキシベンジル基、−ＮＨ−（ＣＨ₂）_a−Ｘ基又は開始剤残基を表し、ここで、ａは１〜５の整数であり、Ｘは、一級、二級、三級アミン又は四級アンモニウム塩の内の１種類又は２種類以上を含むアミン化合物残基、又は、アミンでない化合物残基であり、
ｍは２０〜２，０００の整数であり、
ｎは１〜２００の整数である）
で表されるブロック共重合体であり、前記治療薬が、該ブロック共重合体のＲ^2b及びＲ^2dを介して配位されるか、又は直接若しくはリンカーを介して結合される、項目２に記載の医薬組成物。
［４］ 前記粒径が、２５〜７５ｎｍである、項目１〜３のいずれか一項に記載の医薬組成物。
［５］ 前記治療薬のみで投与された場合に妊婦に対して禁忌となる用法及び／又は用量で前記治療薬が投与される、項目１〜４のいずれか一項に記載の医薬組成物。
［６］ 前記治療薬が、抗癌薬、抗炎症薬、抗高血圧薬、向精神薬からなる群から選ばれる、項目１〜５のいずれか一項に記載の医薬組成物。
［７］ 前記抗癌薬が、白金製剤である、項目６に記載の医薬組成物。
［８］ 前記白金製剤が、前記ブロック共重合体の１又は２個のカルボキシレート基との配位結合を介して形成される、項目７に記載の医薬組成物。
［９］ 前記治療薬が抗炎症薬であり、流産防止用である、項目１〜６のいずれか一項に記載の医薬組成物。
［１０］ 前記抗炎症薬が、非ステロイド性抗炎症剤である、項目９に記載の医薬組成物。
［１１］ 前記治療薬が抗高血圧薬であり、妊娠高血圧薬治療用である、項目１〜６のいずれか一項に記載の医薬組成物。
［１２］ 前記抗高血圧薬が、スタチン系抗高血圧薬である、項目１１に記載の医薬組成物。
［１３］ 前記医薬組成物が、胎児薬害低減用医薬組成物である、項目１〜１２のいずれか一項に記載の医薬組成物。
［１４］ 前記医薬組成物が、胎盤関門透過低減用医薬組成物である、項目１〜１２のいずれか一項に記載の医薬組成物。
［１５］ 以下の一般式（Ｉ）または（ＩＩ）：

（式中、
Ｒ^1a及びＲ^1bは水素原子、水酸基又は未置換もしくは置換された直鎖もしくは分枝のＣ_1-12アルキル基又はＣ_1-12アルコキシ基を表し、
Ｌ¹は−（ＣＨ₂）_b−ＮＨ−を表し、ｂは１〜５の整数であり、
Ｌ²は−（ＣＨ₂）_c−ＣＯ−を表し、ｃは１〜５の整数であり、
Ｒ^2a及びＲ^2ｃは、各出現ごとに独立して、存在しないか、又はメチレン基を表し、
Ｒ^2b及びＲ^2dは、カルボキシ基又は任意のアミノ酸側鎖を表し、
Ｒ³は、水素原子、保護基、疎水性基又は重合性基を表し、
Ｒ⁴は、水酸基、オキシベンジル基、−ＮＨ−（ＣＨ₂）_a−Ｘ基又は開始剤残基を表し、ここで、ａは１〜５の整数であり、Ｘは、一級、二級、三級アミン又は四級アンモニウム塩の内の１種類又は２種類以上を含むアミン化合物残基、又は、アミンでない化合物残基であり、
ｍは２０〜２，０００の整数であり、
ｎは１〜２００の整数である）
で表されるブロック共重合体に、薬物が、該ブロック共重合体のＲ^2b及びＲ^2dを介し、直接またはリンカーを介して結合された薬物複合化ブロック共重合体であって、前記薬物が、インドメタシン又はシンバスタチンである、前記薬物複合化ブロック共重合体。
［１６］ 項目１５に記載音薬物複合化ブロック共重合体により形成されたミセルを含む医薬組成物であって、粒径が、動的光散乱法により測定した場合に２０〜１００ｎｍである、前記医薬組成物。
［１７］ 前記薬物としてインドメタシンを含み、前記医薬組成物が、流産防止用の医薬組成物である、項目１６に記載の医薬組成物。
［１８］ 前記薬物としてシンバスタチンを含み、前記医薬組成物が、妊娠高血圧治療用の医薬組成物である、項目１６に記載の医薬組成物。
［１９］ 治療薬が結合又は配位されたポリエチレングリコール−ポリアミノ酸ブロック共重合体を含み、妊婦又は妊娠可能性のある女性に対し投与するためのミセルの製造方法であって、
前記ポリエチレングリコール−ポリアミノ酸ブロック共重合体を、水中で再構成する工程、及び、
分画分子量１０，０００〜１００，０００の透析膜を用いて限外ろ過を行って、２０〜１００ｎｍの粒径を有するミセルを取得する工程、
を含む、前記製造方法。
［２０］ 前記治療薬が、抗癌薬、抗炎症薬、抗高血圧薬、向精神薬からなる群から選ばれる、項目１９に記載の製造方法。
［２１］ 前記ポリエチレングリコール−ポリアミノ酸ブロック共重合体が、以下の一般式（１−ａ）または（１−ｂ）：

（式中、
Ｒ^1a及びＲ^1bは水素原子、水酸基又は未置換もしくは置換された直鎖もしくは分枝のＣ_1-12アルキル基又はＣ_1-12アルコキシ基を表し、
Ｌ¹は−（ＣＨ₂）_b−ＮＨ−を表し、ｂは１〜５の整数であり、
Ｌ²は−（ＣＨ₂）_c−ＣＯ−を表し、ｃは１〜５の整数であり、
Ｒ^2a及びＲ^2ｃは、各出現ごとに独立して、存在しないか、又はメチレン基を表し、
Ｒ^2b及びＲ^2dは、カルボキシ基又は任意のアミノ酸側鎖を表し、
Ｒ³は、水素原子、保護基、疎水性基又は重合性基を表し、
Ｒ⁴は、水酸基、オキシベンジル基、−ＮＨ−（ＣＨ₂）_a−Ｘ基又は開始剤残基を表し、
ここで、ａは１〜５の整数であり、Ｘは、一級、二級、三級アミン又は四級アンモニウム塩の内の１種類又は２種類以上を含むアミン化合物残基、又は、アミンでない化合物残基であり、
ｍは２０〜２，０００の整数であり、
ｎは１〜２００の整数である）
で表されるブロック共重合体であり、前記治療薬が、前記ブロック共重合体のＲ^2b又はＲ^2dを介して配位されるか、あるいは直接又はリンカーを介して結合される、項目１９又は２０に記載の製造方法。
［２２］ 妊婦又は妊娠可能性のある女性における疾患の治療又は予防に使用するための治療薬が結合又は配位された親水性ポリマーを表面に有する粒子であって、粒径が、動的光散乱法により測定した場合に１０〜１００ｎｍである、前記粒子。
［２３］妊婦又は妊娠可能性のある女性において、流産又は早産の防止、予防又は治療に使用するための抗炎症薬が結合又は配位された親水性ポリマーを表面に有する粒子であって、粒径が、動的光散乱法により測定した場合に１０〜１００ｎｍである、前記粒子。
［２４］妊婦又は妊娠可能性のある女性において、妊娠高血圧の予防又は治療に使用するための抗高血圧薬が結合又は配位された親水性ポリマーを表面に有する粒子であって、粒径が、動的光散乱法により測定した場合に１０〜１００ｎｍである、前記粒子。
［２５］ 胎児の薬害が低減される、項目２２〜２４のいずれか一項に記載の粒子。
［２６］ 胎盤関門透過性が低減される、項目２２〜２４のいずれか一項に記載の粒子。
［２７］ 妊婦又は妊娠可能性のある女性において疾患を治療又は予防する方法であって、妊婦又は妊娠可能性のある女性に、治療薬が結合又は配位された親水性ポリマーを表面に有する粒子を投与することを含み、ここで前記粒子の粒径が、動的光散乱法により測定した場合に１０〜１００ｎｍである、前記方法。
［２８］ 妊婦又は妊娠可能性のある女性において、流産又は早産の防止、予防又は治療するための方法であって、抗炎症薬が結合又は配位された親水性ポリマーを表面に有する粒子を、妊婦又は妊娠可能性のある女性に投与することを含み、ここで粒径が、動的光散乱法により測定した場合に１０〜１００ｎｍである、前記方法。
［２９］ 妊婦又は妊娠可能性のある女性において、妊娠高血圧の予防又は治療するための方法であって、抗高血圧薬が結合又は配位された親水性ポリマーを表面に有する粒子を、妊婦又は妊娠可能性のある女性に投与することを含み、ここで粒径が、動的光散乱法により測定した場合に１０〜１００ｎｍである、前記方法。
［３０］ 胎児の薬害が低減される、項目２７〜２９のいずれか一項に記載の方法。
［３１］ 胎盤関門透過性が低減される、項目２７〜２９のいずれか一項に記載の方法。
［３２］ 妊婦又は妊娠可能性のある女性における疾患の治療又は予防に使用するための医薬の製造のための、治療薬が結合又は配位された親水性ポリマーを表面に有し、粒径が動的光散乱法により測定した場合に１０〜１００ｎｍである粒子の使用。
［３３］ 妊婦又は妊娠可能性のある女性において、流産又は早産の防止、予防又は治療するための医薬の製造のための、治療薬が結合又は配位された粒子であって、親水性ポリマーを表面に有し、粒径が動的光散乱法により測定した場合に１０〜１００ｎｍである粒子の使用。
［３４］妊婦又は妊娠可能性のある女性において、妊娠高血圧の予防又は治療するための医薬の製造のための、治療薬が結合又は配位された粒子であって、親水性ポリマーを表面に有し、粒径が動的光散乱法により測定した場合に１０〜１００ｎｍである粒子の使用。
［３５］ 胎児の薬害が低減される、項目３２〜３４のいずれか一項に記載の使用。
［３６］ 胎盤関門透過性が低減される、項目３２〜３４のいずれか一項に記載の使用。[1] A pharmaceutical composition for administration to a pregnant woman or a woman of childbearing potential, which comprises particles having a hydrophilic polymer on the surface to which a therapeutic agent is bound or coordinated, and has a dynamic particle size. The pharmaceutical composition having a diameter of 10 to 100 nm as measured by a light scattering method.
[2] The pharmaceutical composition according to item 1, wherein the particles are micelles containing a polyethylene glycol-polyamino acid block copolymer.
[3] The polyethylene glycol-polyamino acid block copolymer has the following general formula (I) or (II):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c are independent of each appearance and either do not exist or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amines or quaternary ammonium salts, or a non-amine compound residue.
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
Item 2 is a block copolymer represented by, wherein the therapeutic agent is ^{coordinated via R 2b} and R ^2d of the block copolymer, or is bound directly or via a linker. The pharmaceutical composition described.
[4] The pharmaceutical composition according to any one of items 1 to 3, wherein the particle size is 25 to 75 nm.
[5] The pharmaceutical composition according to any one of items 1 to 4, wherein the therapeutic agent is administered in a dosage and / or dosage contraindicated for a pregnant woman when administered only with the therapeutic agent.
[6] The pharmaceutical composition according to any one of items 1 to 5, wherein the therapeutic agent is selected from the group consisting of an anticancer drug, an anti-inflammatory drug, an antihypertensive drug, and a psychotropic drug.
[7] The pharmaceutical composition according to item 6, wherein the anticancer drug is a platinum preparation.
[8] The pharmaceutical composition according to item 7, wherein the platinum preparation is formed through a coordination bond with one or two carboxylate groups of the block copolymer.
[9] The pharmaceutical composition according to any one of items 1 to 6, wherein the therapeutic agent is an anti-inflammatory agent and is used for preventing miscarriage.
[10] The pharmaceutical composition according to item 9, wherein the anti-inflammatory drug is a non-steroidal anti-inflammatory drug.
[11] The pharmaceutical composition according to any one of items 1 to 6, wherein the therapeutic agent is an antihypertensive agent and is for the treatment of a gestational hypertension agent.
[12] The pharmaceutical composition according to item 11, wherein the antihypertensive drug is a statin-based antihypertensive drug.
[13] The pharmaceutical composition according to any one of items 1 to 12, wherein the pharmaceutical composition is a pharmaceutical composition for reducing fetal phytotoxicity.
[14] The pharmaceutical composition according to any one of items 1 to 12, wherein the pharmaceutical composition is a pharmaceutical composition for reducing placental barrier permeation.
[15] The following general formula (I) or (II):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c independently exist for each appearance or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amines or quaternary ammonium salts, or a non-amine compound residue.
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
A drug-complexed block copolymer in which a drug is bound to the block copolymer represented by (1) ^{via R 2b} and R ^{2d of the block copolymer, directly or via a linker, wherein the drug is.} , Indomethasine or simvastatin, said drug complex block copolymer.
[16] The pharmaceutical composition containing micelles formed from the sound drug complex block copolymer according to item 15, wherein the particle size is 20 to 100 nm when measured by a dynamic light scattering method. Pharmaceutical composition.
[17] The pharmaceutical composition according to item 16, which contains indomethacin as the drug and the pharmaceutical composition is a miscarriage-preventing pharmaceutical composition.
[18] The pharmaceutical composition according to item 16, which comprises simvastatin as the drug and the pharmaceutical composition is a pharmaceutical composition for the treatment of preeclampsia.
[19] A method for producing micelles, which comprises a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated, and is to be administered to pregnant women or women of childbearing potential.
A step of reconstructing the polyethylene glycol-polyamino acid block copolymer in water, and
A step of performing ultrafiltration using a dialysis membrane having a molecular weight cut off of 10,000 to 100,000 to obtain micelles having a particle size of 20 to 100 nm.
The manufacturing method.
[20] The production method according to item 19, wherein the therapeutic agent is selected from the group consisting of an anticancer drug, an anti-inflammatory drug, an antihypertensive drug, and a psychotropic drug.
[21] The polyethylene glycol-polyamino acid block copolymer has the following general formula (1-a) or (1-b):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c independently exist for each appearance or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue.
Here, a is an integer of 1 to 5, and X is an amine compound residue containing one or more of primary, secondary, tertiary amines or quaternary ammonium salts, or a compound that is not an amine. It is a residue
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
A block copolymer represented by, wherein the therapeutic agent is ^{coordinated via R 2b} or R ^2d of the block copolymer, or is bound directly or via a linker, item 19 or. The manufacturing method according to 20.
[22] Particles having a hydrophilic polymer on the surface to which a therapeutic agent for use in the treatment or prevention of a disease in a pregnant woman or a woman of childbearing potential is bound or coordinated, and the particle size is dynamic light. The particles having a diameter of 10 to 100 nm as measured by a scattering method.
[23] Particles having a hydrophilic polymer on the surface to which an anti-inflammatory drug for use in the prevention, prevention or treatment of miscarriage or premature birth is bound or coordinated in a pregnant woman or a woman of childbearing potential. The particles having a diameter of 10 to 100 nm as measured by a dynamic light scattering method.
[24] In pregnant women or women of childbearing potential, particles having a hydrophilic polymer on the surface to which an antihypertensive drug for use in the prevention or treatment of preeclampsia is bound or coordinated, and having a particle size of The particles having a diameter of 10 to 100 nm as measured by a dynamic light scattering method.
[25] The particle according to any one of items 22 to 24, which reduces fetal phytotoxicity.
[26] The particle according to any one of items 22 to 24, wherein the placental barrier permeability is reduced.
[27] A method of treating or preventing a disease in a pregnant or potentially pregnant woman, particles having a hydrophilic polymer on the surface to which a therapeutic agent is bound or coordinated to the pregnant or potentially pregnant woman. The method, wherein the particle size of the particles is 10 to 100 nm as measured by a dynamic light scattering method.
[28] A method for preventing, preventing or treating miscarriage or premature birth in pregnant or potentially pregnant women, the particles having a hydrophilic polymer on the surface to which an anti-inflammatory agent is bound or coordinated. The method described above, comprising administering to a pregnant or potentially pregnant woman, wherein the particle size is 10-100 nm as measured by dynamic light scattering.
[29] In pregnant women or women of childbearing potential, a method for preventing or treating preeclampsia, in which particles having a hydrophilic polymer on the surface to which an antihypertensive drug is bound or coordinated are present on the surface of pregnant women or pregnant women. The method described above, comprising administering to a potential female, wherein the particle size is 10-100 nm as measured by dynamic light scattering.
[30] The method according to any one of items 27 to 29, wherein the fetal phytotoxicity is reduced.
[31] The method according to any one of items 27 to 29, wherein the placental barrier permeability is reduced.
[32] The surface has a hydrophilic polymer to which a therapeutic agent is bound or coordinated and has a particle size for the manufacture of a pharmaceutical for use in the treatment or prevention of a disease in a pregnant woman or a woman of childbearing potential. Use of particles that are 10-100 nm as measured by dynamic light scattering.
[33] Particles to which a therapeutic agent is bound or coordinated to produce a drug for the prevention, prevention or treatment of miscarriage or premature birth in pregnant or potentially pregnant women, the hydrophilic polymer. Use of particles that are on the surface and have a particle size of 10-100 nm as measured by dynamic light scattering.
[34] In pregnant women or women of childbearing potential, particles to which a therapeutic agent is bound or coordinated for the manufacture of a pharmaceutical for the prevention or treatment of preeclampsia, with a hydrophilic polymer on the surface. However, the use of particles whose particle size is 10 to 100 nm when measured by dynamic light scattering.
[35] The use according to any one of items 32 to 34, wherein the fetal phytotoxicity is reduced.
[36] The use according to any one of items 32 to 34, wherein the placental barrier permeability is reduced.

The pharmaceutical composition of the present invention has low placental permeability and can reduce the effect of the medicine on the foetation. This makes it possible to provide a medicine that can be administered to a pregnant woman or a woman who may become pregnant.

FIG. 1 is a photograph showing the accumulation of high molecular weight micelles in the placenta and foetation. FIG. 2 is a photograph showing the analysis of elements (Pt, Fe, K, Ca) after administration of 30 nm-sized micelles. FIG. 3 is a graph showing the platinum content in the foetation of pregnant mice treated with oxaliplatin and dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm). FIG. 4 is a graph showing the platinum content in the placenta of pregnant mice treated with oxaliplatin and dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm). FIG. 5 is a graph showing placental permeability of a drug by a human placental perfusion model. FIG. 5A shows the results for oxaliplatin, 30 nm dahaplatin-encapsulated micelles, 70 nm dahaplatin-encapsulated micelles, and 8-armPEG. FIG. 5B shows the results for 10 nm, 20 nm and 30 nm PEG-coated gold nanoparticles. FIG. 6 is a graph showing the amount of drug accumulated in the human placenta. ^{FIG. 7 shows the 1} H-NMR spectrum of PEG-poly (Asp-Furan-OH). FIG. 8 is a graph showing the stability of micelles in blood and endosome pH. FIG. 9 is a graph showing the amount of indomethacin released in macrophages. FIG. 10 is a graph showing placental permeability of a drug by a human placental perfusion model. FIG. 11 is a diagram showing the tissue transferability of indomethacin-encapsulating polymer micelles. 11A show the location of the recovered organs, and FIGS. 11B-E show the fluorescence of indomethacin-encapsulating polymer micelles 1 hour, 4 hours, 8 hours, and 24 hours after administration. These experiments show that indomethacin micelles are distributed in the liver, kidneys, spleen, uterine body, and placenta, and do not reach the foetation at each point in time. FIG. 12 is a diagram showing an evaluation of the tissue transferability of indomethacin-encapsulating polymer micelles. The amount of indomethacin transferred to (A) kidney, (B) liver, (C) spleen, (D) placenta, and (E) foetation after administration of indomethacin-encapsulating polymer micelles to pregnant mice is shown. It is a graph which shows the survival rate by administration of indomethacin, indomethacin-encapsulating polymer micelle in the preterm mouse model. FIG. 14 is a graph showing changes in blood pressure after administration of a drug in a preeclampsia model mouse. FIG. 15 is a graph showing changes in fetal body weight after administration of a drug in a preeclampsia model mouse. FIG. 16 is a graph showing the amount of urinary albumin after administration of a drug in a preeclampsia model mouse.

The present invention relates to a pharmaceutical composition for administration to a pregnant woman or a woman of childbearing potential. The pharmaceutical composition of the present invention contains particles having a hydrophilic polymer to which a therapeutic agent is bound or coordinated on the surface, and the particle size thereof is 10 to 100 nm when measured by a dynamic light scattering method. It is a feature. From the viewpoint of placental permeability, the particle size is usually 10 nm or more, preferably 20 nm or more, and more preferably 25 nm or more. From the viewpoint of exerting the efficacy of the therapeutic agent, the particle size is usually 100 nm or less, preferably 90 nm or less, more preferably 80 nm or less, and even more preferably 75 nm or less. Particles of this size have low placental permeability and can reduce toxicity to the foetation. In the composition of the present invention, the polydispersity (PDI) of the particle size of the particles is preferably 0.2 or less, and even more preferably 0.1 or less. Since the particles contained in the pharmaceutical composition of the present invention have reduced placental permeability, they can be used as a pharmaceutical composition for reducing fetal phytotoxicity or reducing placental barrier permeability.

Any particles may be used as long as the particles have a hydrophilic polymer on the surface, and micelles and vesicles formed by block copolymers, liposomes whose surface is covered with a hydrophilic polymer, and the like may be used.

（式中、
Ｒ^1a及びＲ^１ｂは水素原子、水酸基、又は未置換もしくは置換された直鎖もしくは分枝のＣ_1-12アルキル基又はＣ_1-12アルコキシ基を表し、
Ｌ¹は−（ＣＨ₂）_b−ＮＨ−を表し、ｂは１〜５の整数であり、
Ｌ²は−（ＣＨ₂）_c−ＣＯ−を表し、ｃは１〜５の整数であり、
Ｒ^2a、及びＲ^2cは、出現ごとに独立して、存在しないか、又はメチレン基を表し、
Ｒ^2b及びＲ^2dは、カルボキシ基又は任意のアミノ酸側鎖を表し、
Ｒ³は、水素原子、保護基、疎水性基又は重合性基を表し、
Ｒ⁴は、水酸基、オキシベンジル基、−ＮＨ−（ＣＨ₂）_a−Ｘ基又は開始剤残基を表し、ここで、ａは１〜５の整数であり、Ｘは、一級、二級、三級アミン又は四級アンモニウム塩の内の１種類又は２種類以上を含むアミン化合物残基、又は、アミンでない化合物残基であり、
ｍは２０〜２，０００の整数であり、
ｎは１〜２００の整数である）
で表されるブロック共重合体を使用することができる。治療薬は、Ｒ^2b及びＲ^2dにおいて、直接またはリンカーを介して結合されるか、又は配位される。As the hydrophilic polymer, any polymer can be used as long as it is a hydrophilic polymer generally used in pharmaceuticals, particularly drug delivery systems. Examples include polyethylene glycol, polylactic acid, polyglycolic acid, polypeptides, polysaccharides and the like. From the viewpoint of producing micelles, polyethylene glycol-polyamino acid block copolymers can be used. As the polyethylene glycol-polyamino acid block copolymer, any known in the art can be used. As the amino acid of the polyethylene glycol-polyamino acid block copolymer, glutamic acid or aspartic acid having a carboxy group in the side chain can be used. As an example, the following general formula (I) or (II):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group, or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c are independent of each appearance and either do not exist or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amines or quaternary ammonium salts, or a non-amine compound residue.
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
Block copolymers represented by can be used. Therapeutic agents are ^{bound or coordinated in R 2b} and R ^2d either directly or via a linker.

Here, in the structural formulas of the general formulas (I) and (II), when the segment having the number of repeating units (degree of polymerization) of "m" is displayed as a PEG-derived uncharged hydrophilic segment (hereinafter referred to as "PEG segment"). The segment whose number of repeating units is "n" is an amino acid-derived segment (hereinafter, may be referred to as "polyamino acid segment").

In the general formulas (I) and (II), R ^1a and R ^1b are independently hydrogen atoms, hydroxyl groups or unsubstituted or substituted linear or branched C _1-12 alkyl groups or C _{1-12, respectively.} Represents an alkoxy group. Linear or branched C _1-12 include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, decyl, undecyl. And so on. When substituted, the substituents include acetalized formyl group, cyano group, formyl group, carboxyl group, amino group, C _1-6 alkoxycarbonyl group, C _2-7 acylamide group, and the same or different tri-C _{1. -6} Alkyl syloxy group, syroxy group or silylamino group can be mentioned. Here, acetalization refers to the reaction of the carbonyl of formyl with, for example, two molecules of an alkanol having 1 to 6 carbon atoms or a branched alkylene diol having 2 to 6 carbon atoms. It means formation and is also a method of protecting the carbonyl group. For example, when the substituent is an acetalized formyl group, it can be hydrolyzed under mild acidic conditions and converted to another substituent, a formyl group (-CHO) (or aldehyde group).

In the general formulas (I) and (II), L ¹ and L ² represent a linking group. Specifically, L ¹ is preferably − (CH ₂ ) _b −NH− (where b is an integer of 1 to 5), and L ² is − (CH _{2 ) c} −CO− (here). And c is an integer of 1 to 5).

In the general formulas (I) and (II), R ^2a and R ^2c do not exist independently at each appearance or represent a methylene group. When aspartic acid is used as the amino acid, dehydration condensation occurs between the carboxy group in the side chain of aspartic acid and the nitrogen in the main chain, and a succinimide intermediate is produced. Cleavage of this intermediate can then result in isomerization to isoaspartic acid. Therefore, when aspartic acid is isomerized to isoaspartic acid, a methylene group is generated at the positions of ^{R 2a} and R ^{2c , and R 2b} and R ^2d become carboxy groups. In the ^{absence of R 2a} and R ^2c, isomerization does not occur, indicating that the amino acid has a peptide bond in the main chain. The rate of isomerization in the block copolymer can be arbitrary. Thus, in the absence of ^{R 2a} and R ^{2c , R 2b} and R ^2d represent any amino acid side and the drug is coordinated via these groups or the drug directly or via a linker. Can be combined. The amino acid side chain may be a side chain of any biological constituent amino acid, but from the viewpoint of binding a drug, it may be a side chain of serine, threonine, arginine, histidine, lysine, cysteine, glutamate and aspartic acid. preferable. When R ^2a and R ^2c are present, R ^2b and R ^2d are carboxy groups. Since the isomerization of aspartic acid to isoaspartic acid in the polyamino acid segment can occur accidentally, the above description is made even when the formula representing only the amide bond between the main chains is described in the present specification. It is not intended to exclude isomerized polymers as in formulas (I) and (II) of. Each repeating unit of amino acid may exist in blocks or may exist randomly.

In the general formulas (I) and (II), R ³ represents a hydrogen atom, a protecting group, a hydrophobic group or a polymerizable group. Specifically, R ³ is preferably an acetyl group, an acryloyl group or a methacryloyl group.

In the general formulas (I) and (II), R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue. Here, a is an integer of 1 to 5, and X is an amine compound residue containing one or more of primary, secondary, tertiary amines or quaternary ammonium salts, or a compound that is not an amine. It is preferably a residue.

In the general formulas (I) and (II), m is an integer of 20 to 2,000, preferably an integer of 40 to 500, and more preferably an integer of 45 to 300. Further, n is an integer of 1 to 200, preferably an integer of 20 to 100, and more preferably an integer of 30 to 50.

Although each repeating unit in the general formulas (I) and (II) is shown in the order specified for convenience of description, each repeating unit may exist in a random order. In particular, it is preferred that only each repeating unit in the polyamino acid segment can be present in random order as described above.

The molecular weight (Mw) of the block copolymers represented by the general formulas (I) and (II) is not limited, but is preferably 5,000 to 40,000, more preferably 8,000 to 22,000. be. For each segment, the molecular weight (Mw) of the PEG segment is preferably 1,000 to 20,000, more preferably 2,000 to 12,000, and the molecular weight of the polyamino acid segment (Mw). ) Is preferably 4,000 to 20,000 as a whole, and more preferably 6,000 to 10,000.

The method for producing the block copolymer represented by the general formulas (I) and (II) is not limited, but for example, ^{a segment (PEG segment) containing R 1a} − or R ^1b − and a block portion of the PEG chain is synthesized in advance. Then, a predetermined monomer is sequentially polymerized on one end of this PEG segment ( ^{the end opposite to R 1a} − or R ^1b −), and then the side chain is substituted so as to contain an anionic group as necessary. Examples thereof include a method of conversion, a method of synthesizing the above-mentioned PEG segment and a block portion having a side chain containing an anionic group in advance, and a method of linking them to each other. The methods and conditions of various reactions in the production method can be appropriately selected or set in consideration of the conventional method. The PEG segment is a method for producing a PEG segment portion of a block copolymer described in, for example, Patent Document 1: WO96 / 32434, Patent Document 2: WO96 / 33233, and Patent Document 3: WO97 / 06202. Can be prepared using.

The bond between the PEG segment portion and the polyamino acid segment portion thus formed can also take an appropriate linking mode depending on the method for producing the block copolymer represented by the general formula (I) or (II), and the present invention As long as it is in line with the object of the invention, it may be bonded at any linking group. The production method is not particularly limited, but as one method for producing the polymer of the general formula (I) or (II), a PEG derivative having an amino group at the terminal is used, for example, from the amino terminal thereof. , Β-benzyl-L-aspartate (BLA), γ-benzyl-L-glutamate and other protected amino acids N-carboxylic acid anhydrides (NCA) are ring-open polymerized to synthesize block copolymers, followed by Examples thereof include a method of converting a chain benzyl group to another ester group, or partially or completely hydrolyzing the group to obtain the desired block copolymer. In this case, the structure of the copolymer is the general formula (I), and the linking group L1 is a structure derived from the terminal structure of the PEG segment used, but is preferably − (CH ₂ ) _b −NH − (here). , B is an integer of 1-5.).

Further, the copolymer of the present invention can also be produced by a method of synthesizing the polyamino acid segment portion and then binding to the PEG segment portion prepared in advance, and in this case, the result is the same as that produced by the above method. _{However, the linking group L 2} is not particularly limited, but is preferably − (CH ₂ ) _c −CO −, as it may have a structure corresponding to the general formula (II). Yes (where c is an integer of 1-5).

Drugs can be bound or coordinated to the hydrophilic polymers of the invention. The agent may be attached to or coordinated with the hydrophilic polymer via a linker or directly. When the hydrophilic polymer is a block copolymer of formula (I) or (II), the agent can be coordinated or bound at ^{R 2b} and R ^2d. When the drug contains a heavy metal such as platinum, the carboxylate group formed by liberating the proton of the carboxy group of the amino acid side chain coordinates with the heavy metal of the drug. When the drug is directly bound, it can be bound via the carboxy group, amino group, thiol group of the amino acid side chain. Any group of the drug can be used for binding, but carboxy groups, amino groups, thiol groups and the like can be used as an example. When attached via a linker, the linker L ₃ can be any linker used in the art, such as C _1-6 alkylene. In yet another embodiment, a drug having a hydrazine reaction with a carboxy group of a polyamino acid or a derivative thereof to form a hydrazide group (in this case, M is -NH-NH ₂ ) and having a ketone via the hydrazide group. May be combined with. In this case, the linker L becomes a hydrazone bond. As the linker that binds the drug to the polyamino acid, any linker known in the art can be used from the viewpoint of producing desired particles.

The therapeutic agent contained in the pharmaceutical composition of the present invention may be any therapeutic agent. Particularly in pregnant women, the required therapeutic agents are mentioned, and as an example, anticancer agents, anti-inflammatory agents, antihypertensive agents, psychotropic agents and the like can be used. Examples of anticancer agents include anticancer agents for treating cancer in any organ such as stomach, skin, larynx, mouth, pharynx, esophagus, digestive organs, pancreas, lung, brain, bone, bone marrow, and breast. Drugs for the treatment of breast cancer, which are more likely to occur in pregnant women.

As the drug used as an anticancer drug, a platinum preparation, an alkylating drug, an antimetabolite drug, a topoisomerase inhibitor, a microtubule inhibitor, an endocrine therapeutic drug and the like can be used. Examples of the platinum preparation include dahaplatin, oxaliplatin, cisplatin, carboplatin and nedaplatin. Platinum preparations are excellent in terms of product development because they can easily detect the accumulation in the foetation. Examples of the alkylating agent include nitrogen mustards such as cyclophosphamide, ifosfamide, melphalan, busulfan and thiotepa, and nitrosoureas such as nimustine, ranimustine, dacarbazine, procarbassine, temozolomide, carmustine, streptzotocin and bendamustine. Antimetabolites include fluorouracil, 6-mercaptopurine, azathioprine, hydroxyurea, thioguanine, fludarabine, cladribine, silatabin, gemcitabine and the like. Examples of topoisomerase inhibitors include camptothecin, irinotecan, nogitecan, anthracycline, doxorubicin, epirubicin, daunorubicin, bleomycin, levofloxacin, cyprofloxacin and the like. Examples of the microtubule polymerization inhibitor include vincristine, vindesine, paclitaxel, docetaxel and the like. Examples of endocrine therapeutic agents include anastrozole, exemestane, tamoxifen, toremifene, fulvestrant, letrozole and the like. In particular, from the viewpoint of using it as a therapeutic agent for breast cancer that frequently occurs in pregnant women, an endocrine therapeutic agent and the like can be mentioned. From the viewpoint of increasing safety, doxorubicin, cyclophosphamide, fluorouracil, etc., which have been proven to have less effect on the foetation, may be used.

In a specific aspect of the invention, the invention relates to a pharmaceutical composition for administration to a pregnant or potentially pregnant woman comprising a dahaplatin derivative micelle coordinated to a polyethylene glycol polyamino acid block copolymer. In this dahaplatin derivative micelle, dahaplatin, which is a partial structure from which the oxalate group of oxaliplatin is removed, is coordinated to the carboxylate group of a polyamino acid (particularly glutamic acid or aspartic acid) instead of the oxalate group, and the micelle size is determined. It is characterized in that it is 10 to 100 nm, preferably 20 to 90 nm, and more preferably 25 to 75 nm. Pharmaceutical compositions containing such dahaplatin derivative micelles may be administered in contraindicated doses and dosages to pregnant or potentially pregnant women when the active agent dahaplatin is administered. As an example, the dahaplatin derivative micelle ^{can be administered at 90-120 mg / m 2} once a week to pregnant or potentially pregnant women.

Anti-inflammatory drugs are non-steroidal anti-inflammatory drugs such as indomethacin, ketoprofen, loxoprofen, diclofenac, ibuprofen, acetylsalicylic acid, celecoxib, etodolac, meroxycam. The pharmaceutical composition of the present invention containing an anti-inflammatory agent can be used as an analgesic and antipyretic drug, a therapeutic agent for rheumatoid arthritis, and can be used for the treatment or prevention of premature birth or miscarriage. Since indomethacin and the like are desired to act in the inflamed area, they can be designed to be released in response to the low pH of the inflamed area. Further, the drug may be designed to be released by the action of esterase possessed by macrophages by being phagocytosed by macrophages in the inflamed area. In addition, the therapeutic agents for diseases that lead to inflammation such as endometriosis, the therapeutic agents for inflammation associated with infectious diseases, and the therapeutic agents for inflammation associated with immunity are also included in the anti-inflammatory agents in this document. be able to.

Examples of hypertensive agents include Ca antagonists, ARBs, ACE inhibitors, diuretics, β-blockers, α-blockers, and statin-based hyperlipidemia agents. Ca antagonists include dihydropyridines such as amlodipine, nifedipine, nicardipine, benidipine, balnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, ephonidipine, cilnidipine, aranidipine, benzothiazepines such as diltiazem, and verapamil. Examples thereof include alkylamine-based agents. Examples of ARB include balsartan, losartan, candesartan, irbesartan, azilsartan and the like. Examples of the ACE inhibitor include imidapril, enalapril, delapril, silazapril, quinapril, temocapril, perindopril, lisinopril, trandolapril and the like. Examples of diuretics include trichloromethiazide, hydrochlorothiazide, furosemide, torasemide, azosemide, spironolactone, triamterene, eplerenone and the like. Examples of the β-blocker include atenolol, bisoprol, betaxolol, metrolol, propranolol, nadolol, nipradilol, carteolol, bindrol, amoslalol, arotinolol, carvedilol, labetalol, bevantolol and the like. Examples of the α blocker include uravidyl, terazosin, prazosin, doxazosin, bunazosin and the like. Examples of statins include simvastatin, pravastatin, lovastatin, pitavastatin, and atorvastatin. The pharmaceutical composition of the present invention including a statin drug can be used as an antihypertensive drug, an antihyperlipidemia drug, a therapeutic or prophylactic drug for preeclampsia. Since statins mainly inhibit cholesterol synthesis in the liver, it is preferable to design them to act in the liver.

In another aspect of the invention, the invention relates to a drug bound to a polyethylene glycol / polyamino acid block copolymer and micelles formed from the block copolymer. Here, the polyethylene glycol / polyamino acid block copolymer is a polyethylene glycol / polyamino acid block copolymer of the formula (I) or (II) defined in the present specification. As the drug bound to the polyethylene glycol / polyamino acid block copolymer, any of the above-mentioned drugs may be used, in particular, indomethacin and simvastatin.

（式中、Ｒ^1a、Ｒ^1b、Ｒ³、Ｒ⁴、ｍ、ｎ、ｂは、本明細書中に定義された通りであり、
ｃは１又は２であり、Ｌ₃は、Ｃ₁−Ｃ₆アルキレンを表す）
本発明に係るインドメタシン結合ブロック共重合体は、水中で自己組織化し、ミセルを形成することができる。When the therapeutic agent is indomethacin, indomethacin is bound via linker L ₃ ^{in R 2b} and R ^2d of the block copolymers described above, and the carboxyl group of indomethacin is bound to _{linker L 3.} As an example, R ^2b and R ^2d are aspartic acid side chains or glutamine side chains, the chemical formulas of which are shown below:

(In the formula, R ^1a , R ^1b , R ³ , R ⁴ , m, n, b are as defined herein.
c is 1 or 2 and L ₃ represents C _{1 −} C ₆ alkylene)
The indomethacin-bound block copolymer according to the present invention can self-assemble in water to form micelles.

（式中、
Ｒ^1a、Ｒ³、Ｒ⁴、ｍ、ｎ、ｂは、本明細書において既に定義された通りであり、
ｋは、導入される架橋の数を表し、ｋは、０〜１９９の整数であり、
ｃは１又は２であり、Ｌ₃は、Ｃ₁−Ｃ₆アルキレンを表す。）。また本発明の別の態様では、フルフリル基が導入された本発明の化合物をミセル化し、１，１−（メチレンジ−４，１−フェニレン）ビスマレイミド（BMI）の添加により架橋されたミセルに関してもよい。From the perspective of forming crosslinks within the micelles, furan may be introduced into some drug binding moieties for crosslinking. The furfuryl group in the cross-linked portion can be further cross-linked in the formation of micelles by further acting on a cross-linking agent such as bismaleimide. The therapeutic agent is indomethacin, and the compound of the present invention into which a flufuryl group has been introduced has the following structure as an example:

(During the ceremony,
R ^1a , R ³ , R ⁴ , m, n, b are as already defined herein.
k represents the number of bridges introduced and k is an integer from 0 to 199.
c is 1 or 2 and L ₃ represents C _{1 −} C ₆ alkylene. ). In another aspect of the present invention, micelles of the present invention having a flufuryl group introduced therein are made into micelles and crosslinked by the addition of 1,1- (methylenedi-4,1-phenylene) bismaleimide (BMI). good.

（式中、
Ｒ^1a、Ｒ³、Ｒ⁴、ｍ、ｎ、ｂは、本明細書において既に定義された通りであり、
ｃは１又は２である）。
本発明の別の態様は、本発明に係るシンバスタチン結合ブロック共重合体を水中で自己組織化して形成させたミセルに関する。If the therapeutic agent is simvastatin, simvastatin can be attached directly to the carboxy group of the side chain of the amino acid by an ester bond. Simvastatin-binding block copolymers are, for example:

(During the ceremony,
R ^1a , R ³ , R ⁴ , m, n, b are as already defined herein.
c is 1 or 2).
Another aspect of the present invention relates to micelles formed by self-assembling the simvastatin-binding block copolymer according to the present invention in water.

The present invention also relates to a method for producing micelles containing a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated. This micelle is predominantly composed of a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated, but may contain any other component as long as the desired size can be achieved. good. Specifically, the method for producing micelles of the present invention is as follows:
A step of reconstitution of a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated in water, and
A step of performing ultrafiltration using a fraction molecular weight 10,000 to 100,000 dialysis membrane to obtain micelles having a particle size of 20 to 100 nm.
including. Further, a step of purifying through a filter having a membrane size of 0.15 to 0.3 may be included. The size of the micelle can be measured by using the dynamic light scattering method.

All references referred to herein are incorporated herein by reference in their entirety.
The embodiments of the present invention described below are for illustration purposes only and do not limit the technical scope of the present invention. The technical scope of the invention is limited only by the description of the claims. Modifications of the present invention, for example, addition, deletion and replacement of the constituent elements of the present invention may be made on condition that the gist of the present invention is not deviated.

Example 1: Evaluation of agglomeration of high molecular weight micelles and low molecular weight compounds of different sizes in the placenta and foetation In this example, the accumulation of high molecular weight micelles and low molecular weight compounds in different sizes in the placenta and foetation was determined by using a pregnancy model mouse. It was evaluated by the fluorescence analysis, elemental analysis and mass spectrometry used.

Preparation of Dahaplatin-encapsulating micelles Two types of fluorescently-labeled dahaplatin-encapsulating micelles (Alexa-555-labeled micelles having a particle size of 30 nm and 70 nm and a particle size of 30 nm and Alexa647-labeled micelles having a particle size of 70 nm) were prepared (Non-Patent Document 2). : H. Cabral et. Al., Nat. Nanotech. 6 (2011) 815-823).

Administration to Pregnancy Model Mice A mixed solution of two types of dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm) was administered to mice on the 14th day after pregnancy. The placenta and foetation were excised 48 hours after administration, and frozen samples were prepared. Then, a frozen section (thickness: 10 mm) was prepared and subjected to nuclear staining with Hoechst. Fluorescence from Hoechst (FIG. 1A) and fluorescence from micelle labels (Alexa 555 and Alexa647) (FIGS. 1B and C) were measured. The distribution of platinum, iron, potassium and calcium in frozen sections of the foetation obtained from pregnant mice administered with dahaplatin-encapsulating micelles (particle size 30 nm) was then measured by synchrotron (Spring-8) (FIG. 2). .. From the results shown in FIG. 1, it was confirmed that two types of dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm) were not accumulated in the foetation (F). In the dahaplatin-encapsulated micelles having a particle size of 30 nm, accumulation in the foetation (F) was not observed, but accumulation of micelles was observed up to the labyrinth (L) layer on the fetal side of the placenta. In the dahaplatin-encapsulated micelle with a particle size of 70 nm, accumulation up to the dedecidua (D) layer on the maternal side of the placenta was observed, but spongy trophoblast cells (spongiotrophoblast) between the D layer and the L layer ( No accumulation in the S) layer was observed. From this result, it was shown that the distribution in the placenta can be controlled by precisely designing the size of the drug. From FIG. 2, it was shown that the passage of the placenta was suppressed by increasing the size of the drug to 30 nm or more because the platinum element derived from dahaplatin was not found in the foetation.

On the 14th day after pregnancy, two types of dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm) and oxaliplatin (8 mg / kg), which is an active form of dahaplatin, were administered, respectively. 48 hours after administration, the placenta and foetation were removed, 1 mL of lysis buffer (Promega, USA) was added to the placenta and foetation after removal, and after homogenization, the platinum element in the tissue was quantified by induced binding plasmon mass spectrometry (Fig. 3). : Foetation, Figure 4: Placenta). From the results shown in FIG. 3, in the foetation of pregnant mice treated with oxaliplatin, the accumulation of platinum in the foetation of platinum was significantly higher than that of the foetation of pregnant mice treated with dahaplatin-encapsulated micelle, and the particle size was 30 nm. It was shown that the above results suppressed the passage of particles through the placenta. From the results shown in FIG. 4, accumulation of platinum in the placenta was observed in the fetuses of pregnant mice treated with oxaliplatin and the fetuses of pregnant mice treated with dahaplatin-encapsulated micelles (particle size 30 nm and 70 nm). Compared with the oxaliplatin-administered group, the accumulation was decreased in the oxaliplatin-administered group of micelles having a particle size of 30 nm, and further decreased in the micelle-administered group having a particle size of 70 nm. From this, it was shown that the accumulation in the placenta can be controlled by precisely designing the size of the drug.

Example 2-1: Evaluation of permeability to human placenta In this example, the permeability of high molecular weight micelles, low molecular weight compounds, and polymers of different sizes in human placenta was evaluated using a human placenta perfusion model.

Preparation of Drugs According to the preparation of the dahaplatin-encapsulating micelles of Example 1, fluorescent-labeled dahaplatin-encapsulating micelles having a particle size of 30 nm and 70 nm were prepared. 8-branched PEG (molecular weight: 40 kDa, 10 nm size (dynamic light scattering method), 20 mg, 0.50 μmol) having an azido group at the terminal was dissolved in DMSO (1.0 mL, 20 mg / mL) and Cy3-DBCO (7). (0.0 mg, 6.0 μmol) was added and reacted at −20 ° C. overnight. Then, dialysis (MWCO: 6,000-8,000) with pure water and freeze-drying gave Cy3-labeled 8armPEG.

Regarding the human placental perfusion model, Non-Patent Document 3 (K. Shintaku et. Al., Drug Metab. Dispos. 37 (2009) 962) Non-Patent Document 4 (JR Huston et. Al., Clin. Pharmacol. Ther. 90 ( 2011) It was prepared according to 67). Specifically, a needle (18 gauge) was introduced into the maternal side of the human placenta provided by the Department of Obstetrics and Gynecology at the University of Tokyo Hospital, and a needle (18 gauge) was introduced into the vein and artery on the fetal side, respectively. The Krebs-Ringer carbonate buffer prepared according to M. Nagai et. Al., Drug Metab. Dispos. 41 (2013) 2124) was perfused at 37 ° C for 30 minutes (maternal flow velocity: 15 mL / min, fetal flow velocity). : 3 ml / min). Here, the buffer was saturated with oxygen generated by the redox reaction of hydrogen peroxide solution and iron chloride. Then, dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm) (dahaplatin dose: 85.4 mg / L), oxaliplatin (2.7 mg / L) and Cy3-labeled 8armPEG (fluorescence intensity: 3,000 (RFU)) were added. Perfusion was performed for 60 minutes, and 1 mL of the solution from the fetal vein was collected every 5 minutes. For the oxaliplatin and dahaplatin-encapsulated micelle-administered groups, the platinum content in the collected samples was measured by inductively coupled plasmon mass spectrometry. For the polymer, the fluorescence intensity was quantified by the HPLC method. The ratio of the permeation amount to the dose of each drug was calculated and shown in FIG. For the oxaliplatin and dahaplatin-encapsulating micelle-administered groups, after the experiment, 2 mL of 90% nitric acid aqueous solution was added to the placenta, dissolved in 2 mL of 1% nitric acid aqueous solution, and the platinum content in the placenta was quantified by induced binding plasmon mass spectrometry. did. The platinum content obtained was standardized by the mass of the placenta (Fig. 6). From the results shown in FIG. 5, oxaliplatin permeated the placenta, but neither dahaplatin-encapsulating micelles (particle size 30 nm and 70 nm) permeated the placenta. It was suggested that it was suppressed. In addition, placental permeation was observed in 8-armPEG, although it was lower than that in oxaliplatin, suggesting that there is a threshold between 10 nm and 30 nm for the size of the drug. From the results shown in FIG. 6, it was shown that oxaliplatin accumulated in the placenta and micelles did not accumulate in the placenta, and thus the accumulation of micelles in the placenta was suppressed due to the difference in placental structure between mice and humans. As a result, it was confirmed that the accumulation and permeation into the placenta can be suppressed by increasing the size of the drug to 30 nm or more.

Example 2-2: Assessment of permeability to human placenta To identify the size of material that passes through the placenta, 10, 20, and 30 nm (5 mL, Nanocs, Inc.) of PEG-coated gold nanoparticles (NP). , USA) was used to perform ex vivo human placental perfusion experiments in the same manner as in Example 2-1. When 10 nm gold NP was perfused, the amount of gold nanoparticles detected from the fetal side increased in a time-dependent manner, reaching 4.58% of the dose after 60 minutes. In addition, when 20 nm Gold NP was perfused, the detected dose from the fetal side was 2.21%. On the other hand, when 30 nm Gold nanoparticles were perfused, the detected dose from the fetal side was 0.05% of the dose after 60 minutes. The results are shown in FIG. 5B. These results suggest that there may be a size cutoff between 20 nm and 30 nm for the material to pass through the placenta.

Example 3: Preparation of indomethacin-encapsulating micelles for the treatment of preterm birth In this example, block copolymer synthesis and micelle preparation were performed for the construction of indomethacin-encapsulating micelles.
Experimental method According to the previously reported (Non-Patent Document 6: M. Yokoyama et. Al., Makromol. Chem. 190 (1989) 2041-2054), an NCA polymerization method using a primary amine of PEG (molecular weight: 12,000 Da) as an initiator. PEG-poly (β-benzyl-L-apartate) (PEG-PVLA) was synthesized. Then, according to the scheme below, PEG-poly (Asp-Fran-OH) (PEG-P (Asp-furan-OH)) was prepared by an aminolysis reaction between 4-amino-1-butanol and 2-aminomethylfuran and the BPLA chain. Synthesized.

Specifically, PEG-PVLA was dehydrated by the benzene freeze-drying method and dissolved in distilled DMF (100 mg / mL). Then, 2 equivalents of distilled 4-amino-1-butanol and 2-aminomethylfuran were added to the BPLA chain, and the mixture was reacted at room temperature for 6 hours. After the reaction, the reaction solution was added to an excess amount of diethyl ether to obtain a polymer. Next, indomethacin was introduced into the polymer by esterifying the hydroxyl group in the polymer with indomethacin. Specifically, dimethylaminopyridine (DMAP), water-soluble carbodiimide (WSC) and indomethacin were mixed (DMAP / WSC / indomethacin = 2: 3: 1 (mass ratio)) and dissolved in DMF (1 mg / mL). .. Then, the solution was added to PEG-P (Asp-furan-OH) so that the molar ratio of indomethacin to BPLA chain was 4, and the reaction was carried out overnight at room temperature. Then, the reaction solution was added to an excess amount of diethyl ether to obtain a polymer. The composition of the obtained polymer ^{was measured by 1} H-NMR. ^{From 1} H-NMR, it was confirmed that the introduction rate of 4-amino-1-butanol was 80% and the introduction rate of 2-aminomethylfuran was 20%.

図7より、ＰＡｓｐ鎖の重合度が３２、インドメタシンの導入量が１６（／ｐｏｌｙｍｅｒ）、フランの導入量が６（／ｐｏｌｙｍｅｒ）であることが確認された。ＤＬＳ測定より、２、７、１４ｍｇ／ｍＬのポリマー濃度で調製したミセルがそれぞれ４１ｎｍ（ＰＤＩ：０．０９）、３７ｎｍ（ＰＤＩ：０．０４）、３９ｎｍ（ＰＤＩ：０．０４）サイズであることが確認され、ミセル調製時のポリマー濃度がミセルのサイズに大きな影響を与えないことが示唆された。また、表１よりＢＭＩ架橋後のサイズが４０ｎｍであったことから、架橋前後でサイズが変化しないことを確認した。Indomethacin-encapsulated micelles were prepared by the dialysis method. The polymer was dissolved in DMSO (2,7,14 mg / mL), dialyzed against pure water (MWCO: 3,500 Da) and purified by a filter (0.22 μm). Then, 1,1- (methylenedi-4,1-phenylene) bismaleimide (BMI) was added to the micelle solution and reacted at 50 ° C. for 2 days. After the reaction, the cells were purified by ultrafiltration (MWCO: 100,000 Da) and a filter (0.22 μm). The size and polydispersity (PDI) of the prepared micelles were measured by dynamic light scattering (DLS).

From FIG. 7, it was confirmed that the degree of polymerization of the PAsp chain was 32, the amount of indomethacin introduced was 16 (/ polymer), and the amount of furan introduced was 6 (/ polymer). From the DLS measurement, micelles prepared at polymer concentrations of 2, 7, and 14 mg / mL are 41 nm (PDI: 0.09), 37 nm (PDI: 0.04), and 39 nm (PDI: 0.04) sizes, respectively. It was confirmed that the polymer concentration at the time of micellar preparation did not significantly affect the micellar size. Moreover, since the size after BMI cross-linking was 40 nm from Table 1, it was confirmed that the size did not change before and after the cross-linking.

Example 4: Stability test of indomethasine-encapsulating micelles In this example, as an index of the stability of indomethasine-encapsulating micelles, the scattered light intensity of the micelle after the addition of the surfactant, and the physiological salt condition and the pH condition in the endosome are used. Indomethacin release was measured.
Experimental method Sodium dodecylsulfonate (SDS), which is one of the surfactants, was added to the micelle solution as an index of stability. Specifically, SDS (20 g) was dissolved in pure water (80 mL) and stirred at 65 ° C. Then, pure water (100 mL) was added to the SDS solution to prepare a 20% SDS aqueous solution. The prepared 20% SDS aqueous solution (10 μL) was added to the micelle solution (70 μL), and after stirring, the size, polydispersity and scattered light intensity (drived count rate (DCR)) were measured by DLS.
In addition, the amount of indomethacin released under physiological salt conditions and endosome pH conditions was used as an index of stability. Specifically, indomethacin-encapsulating micelles were dialyzed against pure water (MWCO: 3,500 Da), and the amount of indomethacin in the sample after dialysis was measured by the HPLC method.

From Table 2, the scattered light intensity of the micelle (NCL) before BMI cross-linking decreased due to the addition of SDS, while the scattered light intensity of the micelle (CL) after cross-linking did not decrease even after the addition of SDS. It was suggested that the stability of micelles was improved. In addition, FIG. 8 showed no release of indomethacin at blood pH (pH 7.4) and endosome pH (pH 5.3), suggesting that indomethacin can be stably included in blood and endosomes. ..

Example 5: Indomethacin release test in macrophages In this example, the release of indomethacin from indomethacin-encapsulating micelles was evaluated by measuring the amount of indomethacin in macrophage cells.

Experimental method For culturing macrophage cells (RAW246.7 cells), cells were seeded at a concentration of 200,000 cells / mL in a 6-well plate for cell culture, and contained 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. Incubated in DMEM for 24 hours. Then, the indomethacin-encapsulating micelles prepared in Example 4 (indomethacin amount: 0.5 mg / mL: micelle diameter: about 40 nm, cross-linked) and indomethacin alone (0.5 mg / mL) were added, respectively, 24, 48, After 72 hours, the cells were washed with PBS and 2% SDS (1 mL) was added to prepare a cell suspension. The amount of indomethacin in the solution was measured by the HPLC method (Fig. 9). From FIG. 9, since the amount of indomethacin released from the indomethacin-encapsulating micelle (CL) is about the same as the amount of uptake of indomethacin alone (FD), the ester bond in the micelle is cleaved by the ester-degrading enzyme in the macrophage, as a result. Efficient release of indomethacin was suggested.

Example 6: Evaluation of permeability to human placenta using indomethacin-encapsulating polymer micelles In this example, the permeability of polymer micelles and low molecular weight compounds of different sizes and polymers in human placenta was measured using a human placenta perfusion model. Evaluated.

Experimental method For the human placental perfusion model, see Non-Patent Document 3 (K. Shintaku et. Al., Drug Metab. Dispos. 37 (2009) 962) Non-Patent Document 4 (JR Huston et. Al., Clin. Pharmacol. Ther. It was prepared according to 90 (2011) 67). Specifically, a needle (18 gauge) was introduced into the maternal side of the human placenta provided by the Department of Obstetrics and Gynecology at the University of Tokyo Hospital, and a needle (18 gauge) was introduced into the vein and artery on the fetal side, respectively. The Krebs-Ringer carbonate buffer prepared according to M. Nagai et. Al., Drug Metab. Dispos. 41 (2013) 2124) was perfused at 37 ° C for 30 minutes (maternal flow velocity: 15 mL / min, fetal flow velocity). : 3 ml / min). Here, the buffer was saturated with oxygen generated by the redox reaction of hydrogen peroxide solution and iron chloride. Then, the indomethacin-encapsulating micelle (indomethacin amount: 2 mg / L: micelle diameter: about 40 nm, cross-linked) prepared in Example 4 and indomethacin alone (2 mg / L) were perfused for 60 minutes, and the solution from the vein on the fetal side. Was collected every 5 minutes. The amount of indomethacin in the collected sample was quantified by the HPLC method (Fig. 10). When indomethacin (IND) was refluxed, the passage rate after 60 minutes was 17.6% (n = 3). On the other hand, when the indomethacin-encapsulating micelle (IND / m) was refluxed, the passage rate after 60 minutes was 0.03% (n = 3) (p <0.05). From the results of FIG. 10, since indomethacin alone permeated the placenta but micelle did not permeate the placenta, it was suggested that the passage of the drug through the human placenta was suppressed by increasing the size of the drug to 30 nm or more. rice field.

Example 6-2: Evaluation of tissue migration of indomethacin-encapsulating polymer micelles Fluorescently labeled indomethacin micelles (IND dose / kg, 10 mg) were administered from the tail vein of pregnant mice on the morning of the 18th and 19th days of pregnancy. After 1 hour, 4 hours, 8 hours, and 24 hours, mice are euthanized and the brain, lung, heart, liver, spleen, pancreas, both kidneys, foetation, umbilical cord, placenta, amniotic membrane, uterine body, The cervix, femoral muscle, and femur were harvested and drug distribution was evaluated using the IVIS imaging system. FIG. 11A shows the location of the recovered organs. 11B-E show fluorescence at 1 hour, 4 hours, 8 hours, and 24 hours after administration. These experiments showed that indomethacin micelles were distributed in the liver, kidneys, spleen, uterine body, and placenta, and did not reach the foetation at each point in time.

Example 6-3: Evaluation of tissue migration of indomethacin-encapsulating polymer micelles Indomethacin (IND dose / kg as 1 mg) and was administered from the tail vein of pregnant mice on the morning of the 18th and 19th days of gestation. After 1 hour, 4 hours, 8 hours, and 24 hours, the mice were euthanized and the foetation, placenta, uterine body, uterus, kidneys, liver and spleen were collected. The sample was homogenized and the indomethacin concentration in the tissue was measured by HPLC. In the indomethacin micelle-administered group, free indomethacin in the tissue and indomethacin in the micellar state were detected as the total amount. This is because indomethacin micelles decompose when sodium hydroxide is used for homogenization. In the free indomethacin group, 0.57% of the maternal dose was detected in the foetation after 24 hours, which was the maximum. On the other hand, in the indomethacin micelle group, only 0.013% of the dose to the mother was distributed to the foetation, which was also the maximum after 24 hours. Therefore, administration of indomethacin micelles significantly reduced (E) distribution to the foetation compared to administration of free indomethacin (p <0.05), thereby preventing indomethacin micelles from crossing the placenta of mice. It has been shown. Furthermore, in organs such as (A) kidney, (B) liver, (C) spleen, and (D) placenta, the amount of indomethacin detected within 24 hours was not sufficient to cause organ damage (Fig. 12A to E).

Example 7: Therapeutic effect of indomethacin-encapsulating micelles using preterm model mice In this example, the preterm birth inhibitory effect and toxicity of indomethacin-encapsulating micelles were evaluated using preterm model mice.

Experimental method Preterm model mice were prepared by administering lipopolysaccharide (LPS) to the cervix according to the previous report (LL Reznikov et. Al., Biol. Reprod. 60 (1999) 1231-1238). Specifically, on the 15th day of pregnancy, LPS (3 μg / mouse) was administered to the vaginal lumen via a soft tube for oral administration of mice.
Then, on the 15th, 16th, 17th, and 18th days of pregnancy, indomethacin-encapsulating micelles (10 mg / kg: micelle diameter: about 40 nm, with / without cross-linking) and indomethacin alone (1 mg / kg) were administered until the 19th day of pregnancy. Delivery was premature. In addition, the abdomen was opened on the 19th day of pregnancy, and the survival rate of the foetation was measured. The results are shown in FIG.

Table 3 showed that administration of micelles and indomethacin alone reduced the number of preterm mice, suggesting that indomethacin suppresses inflammation in the cervical canal. In addition, the administration of micelles increased the survival rate of the foetation, suggesting that the increase in the size of the drug decreased the amount accumulated in the foetation.

Example 8: Preparation of simvastatin-encapsulating micelles for the treatment of preeclampsia In this example, simvastatin was introduced into a block copolymer and micelles were prepared for the treatment of preeclampsia.

ＰＥＧ−ＰＡｓｐをＤＭＦ（１０ｍｇ／ｍＬ）に溶解し、ＰＡｓｐ鎖のカルボキシル基に対して１０当量のＤＭＡＰ、ＥＤＣおよびシンバスタチンを添加し、室温で２４時間反応した。その後、反応溶液を過剰量のジエチルエーテルに添加し、ＰＥＧ−Ｐ（Ａｓｐ−ｓｉｍｖａｓｔａｔｉｎ）を得た。¹Ｈ−ＮＭＲよりシンバスタチンの導入量は１．２ｍｇ／（ｍｇ ｐｏｌｙｍｅｒ）であった。 Experimental method According to Non-Patent Document 7 (A. Harada and K. Kataoka, Macromolecules 28 (1995) 5294-5299), PEG-poly (β) was carried out by an NCA polymerization method using a primary amine of PEG (molecular weight: 12,000 Da) as an initiator. -Benzyl-L-aspartate) (PEG-PVLA) was synthesized, and PEG-poly (L-aspartate) (PEG-PAsp) was synthesized by deprotecting the benzyl group of the side chain structure. Simvastatin was introduced into the polymer by esterification of the carboxyl group of PEG-PAsp and the hydroxyl group of simvastatin according to the scheme below.

PEG-PAsp was dissolved in DMF (10 mg / mL), 10 equivalents of DMAP, EDC and simvastatin were added to the carboxyl group of the PAsp chain, and the reaction was carried out at room temperature for 24 hours. Then, the reaction solution was added to an excess amount of diethyl ether to obtain PEG-P (Asp-simvastatin). ^{1 From 1} H-NMR, the amount of simvastatin introduced was 1.2 mg / (mg polymer).

Simvastatin-encapsulated micelles were prepared by dialysis. The polymer was dissolved in DMAc (1 mg / mL), dialyzed against pure water (MWCO: 3,500 Da), and purified by a filter (0.22 μm). The size and polydispersity (PDI) of the prepared micelles were measured by dynamic light scattering (DLS).

result
^{1 From 1} H-NMR, the amount of simvastatin introduced was 1.2 mg / (mg polymer). In addition, it was confirmed by DLS measurement that micelles having a size of 35 nm and a PDI of 0.23 were obtained.

Example 9: Therapeutic effect and toxicity test of simvastatin-encapsulating micelles using preeclampsia model mice In this example, the antihypertensive effect and toxicity of simvastatin-encapsulating micelles were evaluated using preeclampsia model mice.

Experimental method Preeclampsia model mice were prepared by the method of administering angiotensin II (AngII) according to the previously reported (CC Zhou et. Al., Nat. Med. 14 (2008) 855-862). Specifically, from the 10th day to the 17th day of pregnancy, AngII (1.5 g / kg) was administered to pregnant mice via a subcutaneous pump (flow rate: 1.0 μL / h) to prepare a model of hypertension.

Simvastatin-encapsulating micelles (20 μg / kg: Simvastain Micelle), simvastatin alone (20 μg / kg: Simvastatin), and pravastatin (20 μg / kg: Pravastatin) were administered on the 10th to 17th days of pregnancy, and the drug-free group (NS). The maternal blood pressure, urinary protein content and fetal weight were evaluated in comparison with. Blood pressure was evaluated by a sphygmomanometer on the 10th, 13th, 15th, and 17th days of gestation (Fig. 14). Regarding the body weight of the foetation (FBW (g)), the foetation was removed on the 17th day of pregnancy and the body weight was measured (FIG. 15). For urinary protein, the amount of albumin in urine on days 10, 11, 16 and 17 of pregnancy was measured (FIG. 16).

Results From FIG. 14, since the blood pressure in the drug-administered group was lower than that in the non-administered group, it was confirmed that the blood pressure was decreased by the statin preparation. In addition, the blood pressure of the simvastatin-encapsulated micelle group was similar to that before the administration of Ang II, suggesting the cleavage of the ester bond in the micelle and the resulting sustained release effect of the drug. From FIG. 15, the fetal weight in the simvastatin-encapsulating micelle group (AngiI-Simvastatin Micelle) was similar to that in the Ang II-naive group (NS-NS), suggesting that the placental function was improved by eliminating hypertension. It was also suggested that the size increased due to micelle formation, and as a result, the amount accumulated in the foetation decreased. From FIG. 16, since the increase in urinary albumin amount was suppressed in the simvastatin-encapsulated micelle group, it was suggested that the renal function was improved by eliminating hypertension.

Claims (21)

A pharmaceutical composition for administration to a pregnant woman or a woman of childbearing potential, comprising particles having a hydrophilic polymer on the surface to which a therapeutic agent is bound or coordinated, wherein the particle size is a dynamic light scattering method. The pharmaceutical composition having a diameter of 10 to 100 nm as measured by. The pharmaceutical composition according to claim 1, wherein the particles are micelles containing a polyethylene glycol-polyamino acid block copolymer. The polyethylene glycol-polyamino acid block copolymer has the following general formula (I) or (II):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c , respectively, independently exist at each appearance or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amines or quaternary ammonium salts, or a non-amine compound residue.
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
2. The block copolymer represented by the above, wherein the therapeutic agent is ^{coordinated via R 2b} and R ^2d of the block copolymer, or is bound directly or via a linker. The pharmaceutical composition according to. The pharmaceutical composition according to any one of claims 1 to 3, wherein the particle size is 25 to 75 nm. The pharmaceutical composition according to any one of claims 1 to 4, wherein the therapeutic agent is administered in a dosage and / or dosage contraindicated for a pregnant woman when administered only with the therapeutic agent. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutic agent is selected from the group consisting of an anticancer drug, an anti-inflammatory drug, an antihypertensive drug, and a psychotropic drug. The pharmaceutical composition according to claim 6, wherein the anticancer drug is a platinum preparation. The pharmaceutical composition according to claim 7, wherein the platinum preparation is formed through a coordination bond with one or two carboxylate groups of the amino acid side chain. The pharmaceutical composition according to any one of claims 1 to 6, wherein the therapeutic agent is an anti-inflammatory agent and is used for preventing miscarriage. The pharmaceutical composition according to claim 9, wherein the anti-inflammatory drug is a non-steroidal anti-inflammatory drug. The pharmaceutical composition according to any one of claims 1 to 6, wherein the therapeutic agent is an antihypertensive agent and is used for treating a gestational hypertension agent. The pharmaceutical composition according to claim 11, wherein the antihypertensive drug is a statin-based antihypertensive drug. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition is a pharmaceutical composition for reducing fetal phytotoxicity. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition is a pharmaceutical composition for reducing placental barrier permeation. The following general formula (I) or (II):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c , respectively, independently exist at each appearance or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amines or quaternary ammonium salts, or a non-amine compound residue.
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
A drug-complexed block copolymer in which a drug is bound to the block copolymer represented by (1) ^{via R 2b} and R ^{2d of the block copolymer, directly or via a linker, wherein the drug is.} , Indomethasine or simvastatin, said drug complex block copolymer. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition contains micelles formed from the sound drug complex block copolymer, and the particle size is 20 to 100 nm when measured by a dynamic light scattering method. thing. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition contains indomethacin as the drug, and the pharmaceutical composition is a pharmaceutical composition for preventing miscarriage. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition comprises simvastatin as the drug, and the pharmaceutical composition is a pharmaceutical composition for the treatment of preeclampsia. A method for producing micelles containing a polyethylene glycol-polyamino acid block copolymer to which a therapeutic agent is bound or coordinated and for administration to a pregnant woman or a woman of childbearing potential.
A step of reconstructing the polyethylene glycol-polyamino acid block copolymer in water, and
A step of performing ultrafiltration using a dialysis membrane having a molecular weight cut off of 10,000 to 100,000 to obtain micelles having a particle size of 20 to 100 nm.
The manufacturing method. 19. The production method according to claim 19, wherein the therapeutic agent is selected from the group consisting of an anticancer drug, an anti-inflammatory drug, an antihypertensive drug, and a psychotropic drug. The polyethylene glycol-polyamino acid block copolymer has the following general formula (I) or (II):

(During the ceremony,
R ^1a and R ^1b represent a hydrogen atom, a hydroxyl group or an unsubstituted or substituted linear or branched C _1-12 alkyl group or C _1-12 alkoxy group.
L ¹ represents − (CH ₂ ) _b −NH−, and b is an integer of 1 to 5.
L ² represents − (CH ₂ ) _c −CO−, and c is an integer of 1 to 5.
R ^2a and R ^2c , respectively, independently exist at each appearance or represent a methylene group.
R ^2b and R ^2d represent a carboxy group or any amino acid side chain.
R ³ represents a hydrogen atom, protecting group, hydrophobic group or polymerizable group.
R ⁴ represents a hydroxyl group, an oxybenzyl group, a -NH- (CH ₂ ) _a- X group or an initiator residue, where a is an integer of 1-5 and X is a primary, secondary, An amine compound residue containing one or more of the tertiary amines or quaternary ammonium salts, or a non-amine compound residue.
m is an integer from 20 to 2,000,
n is an integer from 1 to 200)
A block copolymer represented by, wherein the therapeutic agent is ^{bound to the R 2b} and R ^2d groups of the block copolymer, or is bound directly or via a linker-mediated bond. Item 19. The manufacturing method according to Item 19.

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