JP2004300148A - Controlled-release composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a controlled-release composition for oral administration, remarkably improved in persistence of a blood level of an imidazole derivative having steroid C<SB>17,20</SB>lyase inhibiting activity. <P>SOLUTION: This controlled-release composition for the oral administration contains a bioactive substance and a hydrophilic polymer, wherein the bioactive substance comprises a compound expressed by formula (I)-A (Ar is an aromatic ring which may be substituted; and (n) is an integer of 1 to 3) or its salt. Further, the controlled-release composition for the oral administration is formed by coating a core containing the bioactive substance with a coat layer containing the polymer. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to controlled release compositions. More specifically, the present invention relates to a controlled release composition for oral administration containing a steroid C _17,20 lyase inhibitor showing high water solubility under acidic conditions and a hydrophilic polymer, or the steroid C _{17, The present invention} relates to a controlled release composition for oral administration, comprising a core containing a lyase inhibitor and a coating layer containing a polymer.

  Oral dosage forms such as tablets, capsules, and granules are the most frequently used dosage forms in medical practice because they are easy to take and safer than injections and the like. In recent years, for the purpose of improving the quality of life (QOL) of patients and providing labor-saving and economical medical treatment, oral administration preparations that maintain the efficacy for a long time by administration once or twice a day have been developed.

  Drugs that are highly water-soluble under acidic conditions are rapidly eluted and absorbed in the stomach in normal immediate-release preparations, so the duration of effective blood concentration is short, and There is a problem such as the occurrence of toxicity due to a sudden rise in drug concentration. Therefore, there is a strong demand for the development of a controlled-release preparation having a sustained release or non-release in the stomach. However, in some cases, some drugs do not show blood pharmacokinetics in vivo as expected from in vitro dissolution tests, and there are many drugs for which no effective controlled release preparation for oral administration has yet been obtained. is the current situation.

WO 02/40484 pamphlet

An object of the present invention is to contain a steroid C _17,20 lyase inhibitor showing high water solubility under acidic conditions as a physiologically active substance, and the duration of the effective blood concentration of the physiologically active substance has been significantly improved. The purpose of the present invention is to provide a controlled release composition for oral administration.

The present inventors have made intensive studies to achieve the above object, and as a result, a physiologically active substance (for example, a steroid C _17,20 lyase inhibitor or the like) is included in a matrix base composed of a hydrophilic polymer. Alternatively, by coating the nucleus containing the physiologically active substance with a coating layer containing a polymer, the maximum blood concentration is remarkably reduced as compared with an immediate release preparation, and thereafter, the continuous blood concentration is maintained for a long time. It has been found that drug release can be achieved. Furthermore, the nucleus containing the steroid C _17,20 lyase inhibitor is coated with a coating layer containing a polymer that exhibits pH-dependent water solubility, thereby improving the persistence of effective blood concentration. Was successful. The present inventors have further studied based on these findings, and have completed the present invention.

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である生理活性物質と、親水性高分子とを含有する経口投与用放出制御組成物；
〔２〕式：

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である生理活性物質を含有する核を、高分子を含有する被覆層で被覆してなる経口投与用放出制御組成物；
〔３〕日本薬局方崩壊試験の第１液に対する生理活性物質の溶解度（37℃）が約0.1 mg/mL以上である、前記〔１〕または〔２〕記載の放出制御組成物；
〔４〕以下の溶出特性を有することを特徴とする前記〔１〕記載の放出制御組成物：
１）日本薬局方崩壊試験の第１液900 mLを用いた日本薬局方溶出試験法第２法（パドル法、パドルの回転数50 rpm、37℃）において、試験開始15分後における放出制御組成物からの生理活性物質の溶出率が40％未満である、および
２）日本薬局方崩壊試験の第２液900 mLを用いた日本薬局方溶出試験法第２法（パドル法、パドルの回転数50 rpm、37℃）において、試験開始24時間後における放出制御組成物からの生理活性物質の溶出率が40％以上である；
〔５〕(1)式：

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である生理活性物質、(2)ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、カルボキシメチルセルロースナトリウムおよび低置換度ヒドロキシプロピルセルロースから選ばれる親水性高分子および(3)ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる滑沢剤を含有する経口投与用放出制御組成物；
〔６〕以下の溶出特性を有することを特徴とする前記〔２〕記載の放出制御組成物：
１）日本薬局方崩壊試験の第１液900 mLを用いた日本薬局方溶出試験法第２法（パドル法、パドルの回転数50 rpm、37℃）において、試験開始15分後における放出制御組成物からの生理活性物質の溶出率が10％未満である、および
２）日本薬局方崩壊試験の第２液900 mLを用いた日本薬局方溶出試験法第２法（パドル法、パドルの回転数50 rpm、37℃）において、試験開始24時間後における放出制御組成物からの生理活性物質の溶出率が40％以上である；
〔７〕(A)(1)式：

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である生理活性物質および(2)ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、カルボキシメチルセルロースナトリウムおよび低置換度ヒドロキシプロピルセルロースから選ばれる親水性高分子を含有する核を、
(B)(1)セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネートおよびメタクリル酸コポリマーから選ばれる腸溶コーティング剤、(2)ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる滑沢剤および(3)クエン酸アセチルトリブチル、クエン酸アセチルトリエチル、ヒマシ油、ジアセチル化モノグリセリド、セバシン酸ジブチル、フタル酸ジエチル、グリセリン、モノ及びジアセチル化モノグリセリド、ポリエチレングリコール、プロピレングリコール、トリアセチンおよびクエン酸トリエチルから選ばれる可塑剤を含有する被覆層で被覆してなる経口投与用放出制御組成物；
〔８〕被覆層の非存在下における生理活性物質の放出性が速放性である、前記〔２〕記載の放出制御組成物；
〔９〕核が親水性高分子をさらに含んでなる放出制御性マトリックスである、前記〔２〕記載の放出制御組成物；
〔１０〕親水性高分子の含有量が約3重量％〜約95重量％である、前記〔１〕または〔９〕記載の放出制御組成物；
〔１１〕被覆層中の高分子がpH依存型または溶解遅延型の水溶解性を示す、前記〔２〕記載の放出制御組成物；
〔１２〕被覆層中の高分子が水不溶性または水難溶性である、前記〔２〕記載の放出制御組成物；
〔１３〕前記〔１〕または〔２〕記載の放出制御組成物を、該放出制御組成物に含有される生理活性物質と同一もしくは異なる生理活性物質を含有し、且つ該生理活性物質の放出性が速放性である被覆層で被覆してなる放出制御組成物；
〔１４〕前立腺癌または乳癌の予防または治療用である前記〔１〕または〔２〕記載の放出制御組成物；
〔１５〕前記〔１〕または〔２〕記載の放出制御組成物と、該放出制御組成物とは生理活性物質の放出速度が異なる１種以上の他の放出制御組成物とを組み合わせてなる組成物；
〔１６〕他の放出制御組成物が、日本薬局方崩壊試験の第１液に対する溶解度（37℃）が約0.1 mg/mL以上である生理活性物質を含有する前記〔１５〕記載の組成物；
〔１７〕他の放出制御組成物中の生理活性物質が、式：

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である前記〔１６〕記載の組成物；
〔１８〕以下の溶出特性を有することを特徴とする前記〔１７〕記載の組成物：
１）日本薬局方崩壊試験の第１液900 mLを用いた日本薬局方溶出試験法第２法（パドル法、パドルの回転数50 rpm、37℃）において、試験開始15分後における放出制御組成物からの生理活性物質の溶出率が10％未満である、および
２）日本薬局方崩壊試験の第２液900 mLを用いた日本薬局方溶出試験法第２法（パドル法、パドルの回転数50 rpm、37℃）において、試験開始24時間後における放出制御組成物からの生理活性物質の溶出率が20％以上である；
〔１９〕他の放出制御組成物中の生理活性物質の放出性が速放性である前記〔１５〕記載の組成物；
〔２０〕他の放出制御組成物が、生理活性物質を含有する核を、pH依存型または溶解遅延型の水溶解性を示す高分子を含有する被覆層で被覆してなることを特徴とする、前記〔１５〕記載の組成物；
〔２１〕前立腺癌または乳癌の予防または治療用である前記〔１５〕記載の組成物；
〔２２〕(1)(+)-6-(7-ヒドロキシ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-7-イル)-N-メチル-2-ナフタミドもしくはその塩、(2)ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、カルボキシメチルセルロースナトリウムおよび低置換度ヒドロキシプロピルセルロースから選ばれる親水性高分子、(3)乳糖、白糖、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、軽質無水ケイ酸および低置換度ヒドロキシプロピルセルロースから選ばれる崩壊剤、(4)ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる滑沢剤、(5)セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネートおよびメタクリル酸コポリマーから選ばれる腸溶コーティング剤、(6)α化デンプン、ショ糖、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、白糖、D-マンニトール、トレハロース、デキストリン、プルラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースおよびポリビニルピロリドンから選ばれる結合剤および(7)クエン酸アセチルトリブチル、クエン酸アセチルトリエチル、ヒマシ油、ジアセチル化モノグリセリド、セバシン酸ジブチル、フタル酸ジエチル、グリセリン、モノ及びジアセチル化モノグリセリド、ポリエチレングリコール、プロピレングリコール、トリアセチンおよびクエン酸トリエチルから選ばれる可塑剤を含有してなる経口投与用放出制御組成物；
〔２３〕(A)(1)(+)-6-(7-ヒドロキシ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-7-イル)-N-メチル-2-ナフタミドもしくはその塩および(2)ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、カルボキシメチルセルロースナトリウムおよび低置換度ヒドロキシプロピルセルロースから選ばれる親水性高分子を含有する核を、(B)(1)セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネートおよびメタクリル酸コポリマーから選ばれる腸溶コーティング剤、(2)ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる滑沢剤および(3)クエン酸アセチルトリブチル、クエン酸アセチルトリエチル、ヒマシ油、ジアセチル化モノグリセリド、セバシン酸ジブチル、フタル酸ジエチル、グリセリン、モノ及びジアセチル化モノグリセリド、ポリエチレングリコール、プロピレングリコール、トリアセチンおよびクエン酸トリエチルから選ばれる可塑剤を含有する被覆層で被覆してなる経口投与用放出制御組成物などを提供する。 That is, the present invention
[1] Formula:

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a physiologically active substance which is a salt thereof, and a hydrophilic polymer. A controlled release composition for oral administration containing;
[2] Formula:

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a nucleus containing a physiologically active substance which is a salt thereof, A controlled release composition for oral administration coated with a coating layer containing:
[3] The controlled release composition according to [1] or [2], wherein the solubility (37 ° C.) of the physiologically active substance in the first liquid of the Japanese Pharmacopoeia disintegration test is about 0.1 mg / mL or more;
[4] The controlled release composition according to [1], which has the following dissolution characteristics:
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid dissolution test using 900 mL of the first liquid, the release control composition 15 minutes after the start of the test in the second method (paddle method, paddle rotation speed 50 rpm, 37 ° C) The dissolution rate of the physiologically active substance from the substance is less than 40%, and 2) Japanese Pharmacopoeia dissolution test method 2 using 900 mL of the second liquid of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed) (50 rpm, 37 ° C.), the dissolution rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 40% or more;
[5] Equation (1):

(Wherein, n is an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent.) Or a salt thereof, a physiologically active substance, (2) hydroxypropylcellulose, Hydrophilic polymers selected from hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, and (3) magnesium stearate, calcium stearate, talc, light silicic anhydride, colloidal silica, synthetic silicic acid A controlled release composition for oral administration containing a lubricant selected from aluminum and magnesium aluminate metasilicate;
[6] The controlled release composition according to [2], which has the following dissolution characteristics:
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid dissolution test using 900 mL of the first liquid, the release control composition 15 minutes after the start of the test in the second method (paddle method, paddle rotation speed 50 rpm, 37 ° C) The dissolution rate of the physiologically active substance from the substance is less than 10%, and 2) the Japanese Pharmacopoeia dissolution test method 2nd method using 900 mL of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed (50 rpm, 37 ° C.), the dissolution rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 40% or more;
[7] Formula (A) (1):

(Wherein, n is an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent) or a physiologically active substance which is a salt thereof, and (2) hydroxypropylcellulose, Hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and a nucleus containing a hydrophilic polymer selected from low-substituted hydroxypropylcellulose,
(B) (1) cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (2) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloid Lubricants selected from silica, synthetic aluminum silicate and magnesium metasilicate aluminate and (3) acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono And a coating layer containing a plasticizer selected from diacetylated monoglyceride, polyethylene glycol, propylene glycol, triacetin and triethyl citrate. For oral administration controlled release composition comprising overturned;
[8] the controlled release composition of the above-mentioned [2], wherein the release of the physiologically active substance in the absence of the coating layer is immediate release;
[9] The controlled release composition according to [2], wherein the core is a controlled release matrix further comprising a hydrophilic polymer;
[10] The controlled-release composition of the above-mentioned [1] or [9], wherein the content of the hydrophilic polymer is about 3% by weight to about 95% by weight;
[11] The controlled release composition according to the above [2], wherein the polymer in the coating layer exhibits pH-dependent or delayed-solution type water solubility;
[12] The controlled release composition according to [2], wherein the polymer in the coating layer is water-insoluble or hardly water-soluble;
[13] The controlled release composition according to [1] or [2], which contains the same or different bioactive substance as the bioactive substance contained in the controlled release composition, and has a release property of the bioactive substance. Is a controlled release composition coated with a coating layer that is immediate release;
[14] the controlled-release composition of the above-mentioned [1] or [2], which is used for prevention or treatment of prostate cancer or breast cancer;
[15] A composition comprising a combination of the controlled release composition according to the above [1] or [2] and one or more other controlled release compositions having different release rates of a physiologically active substance from the controlled release composition. object;
[16] The composition of the above-mentioned [15], wherein the other controlled release composition contains a physiologically active substance having a solubility (37 ° C.) in the first liquid of the Japanese Pharmacopoeia disintegration test of about 0.1 mg / mL or more;
[17] The bioactive substance in the other controlled release composition is represented by the formula:

(Wherein n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a salt thereof, wherein the composition according to the above [16],
[18] The composition according to the above [17], which has the following elution characteristics:
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid dissolution test using 900 mL of the first liquid, the release control composition 15 minutes after the start of the test in the second method (paddle method, paddle rotation speed 50 rpm, 37 ° C) The dissolution rate of the physiologically active substance from the substance is less than 10%, and 2) the Japanese Pharmacopoeia dissolution test method 2nd method using 900 mL of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed (50 rpm, 37 ° C), the dissolution rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 20% or more;
[19] the composition of the above-mentioned [15], wherein the release of the physiologically active substance in the other controlled release composition is immediate release;
[20] The other controlled release composition is characterized in that a nucleus containing a physiologically active substance is coated with a coating layer containing a pH-dependent or dissolution-delayed water-soluble polymer. The composition of [15];
[21] the composition of the above-mentioned [15], which is for prevention or treatment of prostate cancer or breast cancer;
[22] (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or a salt thereof , (2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, hydrophilic polymer selected from sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, (3) lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium Disintegrant selected from croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted hydroxypropylcellulose, (4) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic silica Aluminum oxide (5) cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (6) pregelatinized starch, A binder selected from sugar, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone; and (7) Acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglyceride, SEBASHI Dibutyl, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, oral controlled release composition comprising a plasticizer selected from triacetin and triethyl citrate;
[23] (A) (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide Or a salt thereof and (2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, a nucleus containing a hydrophilic polymer selected from sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, (B) (1) cellulose Acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (2) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate and Aluminum metasilicate Lubricant selected from magnesium and (3) acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono and diacetylated monoglyceride, polyethylene glycol, propylene glycol, Provided is a controlled release composition for oral administration which is coated with a coating layer containing a plasticizer selected from triacetin and triethyl citrate.

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩を含有し、親水性高分子を含有してなる経口投与用放出制御組成物を提供する。
本明細書において「経口投与用放出制御組成物」とは、該組成物中に含まれる生理活性物質の経口投与後の放出プロファイルが、該生理活性物質自体の投与におけるそれとは異なるように制御された組成物をいい、放出速度がより低く制御（徐放化）されたもの、より大きく制御（溶解促進）されたもの、および放出開始時期が制御（溶解遅延）されたもののいずれをも包含し、さらにはそれらの2以上の制御を組み合わせたものも包含する。また、溶出の過程全体にわたって放出が制御される必要はなく、その一部において放出が制御されてさえいれば、本発明の経口投与用放出制御組成物（以下、単に「放出制御組成物」という場合もある）に包含される。 The present invention relates to a bioactive substance represented by the formula:

Wherein n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent, or a salt thereof, and a hydrophilic polymer. Provided is a controlled release composition for oral administration.
As used herein, the term "controlled release composition for oral administration" means that the release profile of a physiologically active substance contained in the composition after oral administration is controlled to be different from that in the administration of the physiologically active substance itself. A controlled release (controlled release), a controlled release (promoted dissolution), and a controlled release start time (dissolution delay). And also a combination of these two or more controls. Further, it is not necessary to control the release throughout the dissolution process, and if only a part of the release is controlled, the controlled release composition for oral administration of the present invention (hereinafter simply referred to as “controlled release composition”) In some cases).

（式中、m1は1ないし4の整数を、m2は0ないし3の整数を示し、Ra¹およびRa²は同一または異なって、水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール、置換基を有していてもよいアミノ、アシル、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基、式：

（式中、m3は1ないし5の整数を、m4は0ないし4の整数を示し、Ra³およびRa⁴は同一または異なって、水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール、置換基を有していてもよいアミノ、アシル、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基または式：

（式中、m5は1ないし4の整数を示し、Ra⁵は水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール、置換基を有していてもよいアミノ、アシル、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基である化合物、
〔４〕式中、Arが式：

（式中、Ra⁶およびRa⁷は同一または異なって、水素原子または低級アルキルを示す）で表される基または、式：

（式中、m4は0ないし4の整数を示し、Ra³およびRa⁴は同一または異なって、水素原子、置換基を有していてもよい水酸基、置換基を有していてもよいチオール、置換基を有していてもよいアミノ、アシル、ハロゲン原子または置換基を有していてもよい炭化水素基を示す）で表される基である化合物、
〔５〕式中、Arが式：

（式中、Ra⁶およびRa⁷は同一または異なって、水素原子または低級アルキルを示す）で表される基である化合物、
〔６〕立体配置がS配置のエナンチオマーである化合物、および
〔７〕立体配置がR配置のエナンチオマーである化合物。 Preferred examples of the compound represented by the formula (I) -A include the following compounds:
[1] In the formula, a compound wherein Ar is a monocyclic or bicyclic aromatic condensed ring which may have a substituent,
[2] In the formula, a compound wherein Ar may be substituted, and is an aromatic ring composed of 5 to 10 atoms including 0 to 4 heteroatoms as ring-constituting atoms and bonded by a carbon atom,
[3] In the formula, Ar is a formula:

(In the formula, m1 represents an integer of 1 to 4, m2 represents an integer of 0 to 3, Ra ¹ and Ra ² are the same or different and are each a hydrogen atom, a hydroxyl group which may have a substituent, a substituent A thiol which may have a substituent, an amino which may have a substituent, an acyl, a halogen atom or a hydrocarbon group which may have a substituent).

(In the formula, m3 represents an integer of 1 to 5, m4 represents an integer of 0 to 4, Ra ³ and Ra ⁴ are the same or different and are each a hydrogen atom, a hydroxyl group which may have a substituent, a substituent Represents a thiol which may have, an amino which may have a substituent, an acyl, a halogen atom or a hydrocarbon group which may have a substituent) or a group represented by the formula:

(In the formula, m5 represents an integer of 1 to 4, Ra ⁵ represents a hydrogen atom, a hydroxyl group optionally having a substituent, a thiol optionally having a substituent, A good amino, acyl, a halogen atom or a hydrocarbon group which may have a substituent)).
[4] In the formula, Ar is a formula:

Wherein Ra ⁶ and Ra ⁷ are the same or different and each represent a hydrogen atom or lower alkyl, or a group represented by the formula:

(In the formula, m4 represents an integer of 0 to 4, Ra ³ and Ra ⁴ are the same or different, and each is a hydrogen atom, a hydroxyl group which may have a substituent, a thiol which may have a substituent, Represents an amino, acyl, halogen atom or a hydrocarbon group optionally having a substituent) which may have a substituent),
[5] In the formula, Ar is a formula:

(Wherein, Ra ⁶ and Ra ⁷ are the same or different and each represent a hydrogen atom or a lower alkyl),
[6] a compound whose configuration is an S-enantiomer, and [7] a compound whose configuration is an R-enantiomer.

The definition of each symbol in each formula is as follows.
n is an integer of 1 to 3, preferably 1.
m1 is an integer of 1 to 4, preferably 1 or 2, and particularly preferably 1.
m2 is an integer of 0 to 3, preferably 0 or 1, and particularly preferably 0.
m3 is an integer of 1 to 5, preferably 1 to 3, and particularly preferably 1.
m4 is an integer of 0 to 4, preferably 0 or 1, and particularly preferably 0.
m5 is an integer of 1 to 4, preferably 1 or 2, and particularly preferably 1.
m6 is an integer of 0 to 3, preferably 0 or 1, and particularly preferably 0.

Examples of the optionally substituted hydroxyl group represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, in addition to unsubstituted hydroxyl groups, lower alkoxy (eg, methoxy, ethoxy, propoxy and the like) C _1-4 alkoxy), lower alkanoyloxy (eg, acetyloxy, C _1-4 alkanoyloxy such as propionyloxy), carbamoyloxy optionally having a substituent (eg, unsubstituted carbamoyloxy, Examples thereof include carbamoyloxy substituted with one or two C _1-4 alkyl such as methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy, and ethylmethylcarbamoyloxy.
Examples of the thiol which may have a substituent represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, in addition to unsubstituted thiol, lower alkylthio (eg, methylthio, ethylthio, propylthio and the like) C _1-4 alkylthio), lower alkanoylthio (eg, C _1-4 alkanoylthio such as acetylthio and propionylthio) and the like.
Examples of the optionally substituted amino represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, in addition to unsubstituted amino, lower alkylamino (eg, methylamino, ethylamino, C _1-4 alkylamino such as propylamino), di-lower alkylamino (eg, di-C _1-4 alkylamino such as dimethylamino, diethylamino), C _1-4 alkanoylamino (eg, acetylamino, propionylamino, etc.) And the like.
Examples of the acyl represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, for example, alkanoyl (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl) and alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl) C _1-4 alkylsulfonyl) etc., aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.), carbamoyl which may have a substituent (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, of diethylcarbamoyl and mono- - Or di-C _1-10 alkylcarbamoyl, for example, mono- or di-C _6-14 arylcarbamoyl such as phenylcarbamoyl, diphenylcarbamoyl, for example, mono- or di-C _7-16 aralkylcarbamoyl such as benzylcarbamoyl, dibenzylcarbamoyl. Etc.), optionally substituted Famoiru (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, mono- such as diethyl sulfamoyl - or di -C _1-10 alkylsulfamoyl, for example, phenyl sulfamoyl, diphenyl sulfamoyl etc. Mono- or di-C _6-14 arylsulfamoyl, for example, benzylsulfamoyl, dibenzylsulfamoyl and the like mono- or di-C _7-16 aralkylsulfamoyl and the like).
Examples of the halogen represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include fluorine, chlorine, bromine and iodine.
Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ include, for example, a chain hydrocarbon group or a cyclic hydrocarbon group. And a hydrogen group.

Examples of the chain hydrocarbon group include a linear or branched chain hydrocarbon group having 1 to 10 carbon atoms, and specific examples include alkyl, alkenyl, alkynyl and the like. Of these, alkyl is particularly preferred. Examples of the `` alkyl '' include C <sub>1-10</sub> alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc. C <sub>1-6</sub> alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, etc.) is preferred. Examples of the "alkenyl", for example vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, but C <sub>2-10</sub> alkenyl such as sec- butenyl C <sub>2 -6</sub> alkenyl (eg, vinyl, 1-propenyl, allyl, etc.) is preferred. Examples of the “alkynyl” include C <sub>2-10</sub> alkynyl such as ethynyl, 1-propynyl, and propargyl, and C <sub>2-6</sub> alkynyl (eg, ethynyl) is preferable.
Examples of the cyclic hydrocarbon group include a cyclic hydrocarbon group having 3 to 18 carbon atoms, and specific examples include an alicyclic hydrocarbon group and an aromatic hydrocarbon group.
As the "alicyclic hydrocarbon group", for example, a monocyclic or condensed polycyclic group composed of 3 to 10 carbon atoms, specifically, cycloalkyl, cycloalkenyl and C <sub>6- And</sub> bicyclic or tricyclic fused rings with <sub>14</sub> aryl (eg, benzene and the like). Examples of the `` cycloalkyl '' include C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and examples of the `` cycloalkenyl '' include C <sub>3-6</sub> such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. <sub>3-6</sub> cycloalkenyl and the like.
Examples of the `` aromatic hydrocarbon group '' include a monocyclic aromatic hydrocarbon group composed of 6 to 18 carbon atoms, a condensed polycyclic aromatic hydrocarbon group, and the like. And C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, and 2-anthryl, and C _6-10 aryl (eg, phenyl and the like) is preferable.

  Examples of the substituent which the “chain hydrocarbon group” in the “hydrocarbon group optionally having” may have include, but are not particularly limited to, for example, a halogen atom, a hydroxyl group, an alkoxy group, an acyloxy group. , Alkylthio, acylamino, carboxyl, alkoxycarbonyl, oxo, alkylcarbonyl, cycloalkyl, aryl, aromatic heterocyclic groups and the like. These substituents are substituted on the “chain hydrocarbon group” within the range chemically permitted, and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of substituents is two or more, they may be the same or different.

  The substituent which the “cyclic hydrocarbon group” in the “hydrocarbon group optionally having” may have is not particularly limited, and is, for example, a halogen atom, a hydroxyl group, an alkoxy group, an acyloxy group. , Alkylthio, alkylsulfonyl, mono- or di-alkylamino, acylamino, carboxyl, alkoxycarbonyl, alkynylcarbonyl, alkyl, cycloalkyl, aryl, aromatic heterocyclic groups and the like. These substituents are substituted on the “cyclic hydrocarbon group” within the range chemically permitted, and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of substituents is two or more, they may be the same or different.

Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. Examples of the “alkoxy” include C _1-10 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy. Examples of the “acyloxy” include formyloxy, C _1-10 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.). Examples of the "alkylthio", for example, methylthio, ethylthio, propylthio, C _1-10 alkylthio such as isopropylthio and the like. Examples of the “alkylsulfonyl” include C _1-10 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, and propylsulfonyl. Examples of the “acylamino” include formylamino, diformylamino, mono- or di-C _1-10 alkyl-carbonylamino (eg, acetylamino, propionylamino, butyrylamino, diacetylamino, etc.). Examples of the “mono- or di-alkylamino” include the same as the above-mentioned lower alkylamino and di-lower alkylamino. Examples of the “alkoxycarbonyl” include C _1-10 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl. Examples of the “alkylcarbonyl” include C _1-10 alkylcarbonyl such as acetyl, propionyl, butyryl, valeryl and the like. Examples of the “alkynylcarbonyl” include C _3-10 alkynylcarbonyl such as ethynylcarbonyl, 1-propynylcarbonyl and 2-propynylcarbonyl. Examples of the “cycloalkyl” include C _3-10 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of the “aryl” include C _6-14 aryl such as phenyl, 1-naphthyl and 2-naphthyl. As the "aromatic heterocyclic group", for example, other than carbon atoms, one or two heteroatoms selected from nitrogen, oxygen and sulfur, preferably 1 to 3 cyclic aromatic heterocyclic group containing 1 to 4 And the like. Specific examples include thienyl, pyridyl, furylpyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridazinyl, tetrazolyl, quinolyl, indolyl, isoindolyl and the like. Examples of the “alkyl” include C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and pentyl.

The substituent which the `` hydrocarbon group '' may have further has 1 to 5, preferably 1 to 3 substituents as shown below in a chemically acceptable range. Is also good. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine), a hydroxyl group, and C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.).

The lower alkyl represented by Ra ⁶ and Ra ⁷ represents, for example, a linear, branched or cyclic alkyl having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, tert-butyl, cyclopropyl, cyclobutyl and the like.

The optionally substituted aromatic ring represented by Ar is exemplified by a monocyclic or bicyclic aromatic condensed ring optionally having one or more substituents. Further, an aromatic ring which may be substituted and is composed of 5 to 10 atoms including 0 to 4 heteroatoms as ring-constituting atoms (where the aromatic ring is not a heteroatom but a carbon atom and has the formula ( I) bonded to the condensed imidazole ring in -A) is also suitably exemplified as Ar.
As the substituent in the optionally substituted aromatic ring represented by Ar, a hydroxyl group which may have a substituent, a thiol which may have a substituent, and a substituent which may have a substituent Examples thereof include an amino, acyl, halogen atom or a hydrocarbon group which may have a substituent. The "optionally substituted hydroxyl group", the "optionally substituted amino group", the "acyl", the "halogen atom" and the "optionally substituted group" Examples of the “hydrocarbon group” include those exemplified above for Ra ¹ , Ra ² , Ra ³ , Ra ⁴ and Ra ⁵ .

The compound represented by the formula (I) -A may form a salt, and the salt may be an acid addition salt such as an inorganic acid salt (eg, hydrochloride, sulfate, hydrobromide, phosphorus Acid salts, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methane) Sulfonate, p-toluenesulfonate, etc.).
In addition, the compound represented by the general formula (I) -A or a salt thereof may be a hydrate, and both are within the scope of the present invention. Hereinafter, the term "compound (I) -A" includes salts and hydrates.

The compound represented by the formula (I) -A and a prodrug thereof have excellent effects as pharmaceuticals, and particularly have an excellent inhibitory activity against steroid C _17,20 lyase. Since these compounds have low toxicity and few side effects, they are useful for mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, etc., particularly humans), for example, (i) androgen or Estrogen-lowering drugs [i.e., drugs having an effect of suppressing the production of androgens and the subsequent production of estrogen (estrogens are synthesized using androgens as substrates)], (ii) diseases related to androgens or estrogens, for example, (1) malignant tumors (eg, prostate cancer, breast cancer, uterine cancer, ovarian cancer, etc.) primary cancer, metastasis or recurrence, (2) symptoms associated with those cancers (eg, pain, cachexia, etc.), ( 3) Various types such as prostatic hypertrophy, virilization, hirsutism, male pattern baldness, precocious boyhood, endometriosis, uterine fibroids, uterine adenomyosis, mastopathy, polycystic ovary syndrome, etc. It is useful as an agent for treating and preventing diseases, preferably prostate cancer and breast cancer.

The prodrug of compound (I) -A refers to a compound that is converted into compound (I) -A by a reaction with an enzyme, gastric acid, or the like in a living body. Since the prodrug exhibits steroid C _17,20 lyase inhibitory activity by being converted into compound (I) -A in vivo, it is included in the physiologically active substance contained in the controlled release composition of the present invention. Shall be
Examples of the prodrug of compound (I) -A include compounds in which imidazole nitrogen of compound (I) -A is acylated or alkylated (eg, dimethylaminosulfonylation, acetoxymethylation, (5-methyl-2-oxo) -1,3-dioxolen-4-yl) methoxycarbonylmethylated, pivaloyloxymethylated, benzyloxymethylated compounds, etc.); the hydroxyl group of compound (I) -A is acylated, alkylated, phosphorylated , Sulfated, borated compounds (eg, compounds in which the hydroxyl group of compound (I) -A is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated) Etc.). These compounds can be produced by a method known per se.
The prodrug of compound (I) -A may be itself or a pharmacologically acceptable salt. Such salts include, when the prodrug of compound (I) -A has an acidic group such as carboxyl, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc). , Iron, copper, etc.) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, tromethamine [tris (hydroxy Methyl) methylamine], organic amines such as tert-butylamine, and basic amino acids such as arginine, lysine, ornithine, etc.).

When the prodrug of compound (I) -A has a basic group such as amino, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, triionic acid) With acidic amino acids such as fluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid, glutamic acid, etc. Salts.
Further, the prodrug of compound (I) -A may be either a hydrate or a non-hydrate.
Compound (I) -A has one or more asymmetric carbons in the molecule, and both R configuration and S configuration with respect to these asymmetric carbons are included in the present invention.
As the compound (I) -A, a compound in which the absolute configuration of the carbon atom to which a hydroxyl group is bonded is S configuration is preferable.

  Among the compounds represented by the formula (I) -A, (±) -7- (5-methoxybenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2 -c] Imidazol-7-ol, (±) -7- (5-fluorobenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-7- All, (±) -7- (4′-fluoro [1,1′-biphenyl] -3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, ±) -7- (4'-Fluoro [1,1'-biphenyl] -4-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (±)- 6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide, (±) -N-cyclopropyl-6- ( 7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, (±) -N-ethyl-6- (7-hydroxy-6,7- Dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, (±) -N-cyclobutyl-6- (7-hydroxy-6, 7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, (±) -6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2- c] Imidazol-7-yl) -N-isopropyl-2-naphthamide, (±) -6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) 2-naphthamide, (+)-7- (5-methoxybenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (+ ) -7- (5-Fluorobenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (+)-7- (4 ′ -Fluoro [1,1′-biphenyl] -3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (+)-7- (4′-fluoro [ 1,1'-biphenyl] -4-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (+)-6- (7-hydroxy-6,7- Dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide, (+)-N-cyclopropyl-6- (7-hydroxy -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, (+)-N-ethyl-6- (7-hydroxy-6,7-dihydro-5H -Pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, (+)-N-cyclobutyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c ] Imidazol-7-yl) -2-naphthamide, (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-isopropyl- 2-naphthamide, (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, (-)-7- (5 -Methoxybenzo [b] thiophen-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (-)-7- (5-fluorobenzo [b] thiophene -2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (-)-7- (4'-fluoro [1,1'-biphenyl] -3- Yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (-)-7- (4'-fluoro [1,1'-biphenyl Ru] -4-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol, (-)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide, (-)-N-cyclopropyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1, 2-c] imidazol-7-yl) -2-naphthamide, (-)-N-ethyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-7- Yl) -2-naphthamide, (-)-N-cyclobutyl-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide, -)-6- (7-Hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-isopropyl-2-naphthamide, (-)-6- (7- Hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -2-naphthamide and the like are preferred. Particularly, (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide is preferable.

  The compound represented by the formula (I) -A can be produced, for example, by the method disclosed in WO 02/40484.

  Preferably, the physiologically active substance contained in the controlled release composition of the present invention has high water solubility under acidic conditions, and specifically, the first liquid of the Japanese Pharmacopoeia disintegration test at 37 ° C. Solubility (hereinafter sometimes abbreviated as "solubility (1 solution, 37 ° C)") to about 0.1 mg / mL or more, preferably about 1 mg / mL or more, more preferably about 5 mg / mL or more. belongs to.

The `` hydrophilic polymer '' contained in the controlled release composition of the present invention becomes a hydrogel by absorbing water, and diffuses a physiologically active substance dispersed in the gel, or immerses itself in water. It means a polymer which can control the release of a physiologically active substance by dissolving, or which is insoluble in water and swells to control the release of the physiologically active substance.
The viscosity of the hydrophilic polymer is, for example, preferably 1 mPa · s or more, more preferably 4 mPa · s or more, as the viscosity of a 2% by weight aqueous solution (measuring temperature: 20 ° C.). In the controlled release composition of the present invention, the release period of the physiologically active substance from the composition is arbitrarily adjusted by adjusting the viscosity of the hydrophilic polymer used as the controlled release base and the compounding ratio thereof. can do.

Specific examples of the hydrophilic polymer include HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 2.0 to 2.9 mPa · s), HPC-SL (trade name, (Manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 3.0 to 5.9 mPa · s), HPC-L (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C.) : 6.0 to 10.0 mPa · s), HPC-M (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 150 to 400 mPa · s), HPC-H (trade name, Nippon Soda) Hydroxypropylcellulose such as (viscosity of a 2% by weight aqueous solution at 20 ° C .: 1000 to 4000 mPa · s);
TC-5E (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 3 mPa · s), TC-5EW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C.) Of a 2% by weight aqueous solution at about: 3 mPa · s), SB-4 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 4 mPa · s), TC-5MW ( Brand name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4.5 mPa · s) TC-5R (brand name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2% by weight at 20 ° C.) Viscosity of aqueous solution: about 6 mPa · s), TC-5RW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 6 mPa · s), TC-5S (trade name, Shin-Etsu) (Manufactured by Chemical Industry Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 15 mPa · s), Metrolose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C.) : About 50mPa ・ s), Metro 6565SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 50 mPa · s); Metrolose 90SH-100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) Viscosity of a 2% by weight aqueous solution at 20 ° C .: about 100 mPa · s), Metrolose 65SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metrolze 90SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metroz 65SH-1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 Viscosity of 2% by weight aqueous solution at ℃: about 1500 mPa · s), Metrolose 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% by weight aqueous solution at 20 ° C: about 4000 mPa · s), Metrolse 65SH -4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metroze 90SH-4 000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose 90SH-30000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (at 20 ° C.) Viscosity of a 2% by weight aqueous solution: about 30 000 mPa · s) such as hydroxypropyl methylcellulose;
Metrolose SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity: about 15 mPa · s, 2% by weight aqueous solution, 20 ° C), Metrolose SM25 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 at 20 ° C) Viscosity of aqueous solution by weight: about 25 mPa · s), Metrolose SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: about 100 mPa · s), Metrolose SM400 (brand name, Shin-Etsu) (Manufactured by Chemical Industry Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metrolose SM1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 1500 mPa · s), Metrolose SM4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose SM8000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of a 2% by weight aqueous solution at 20 ° C .: about 8000 mPa · s);
WSR N-12K (trade name, manufactured by Union Carbide Co.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 400 to 800 mPa · s), WSR N-60K (trade name, manufactured by Union Carbide Co.) (2 weight at 20 ° C.) % Aqueous solution: 2000-4000 mPa · s), WSR 301 (trade name, manufactured by Union Carbide) (viscosity of 1% by weight aqueous solution at 25 ° C .: 1500-4500 mPa · s), WSR Coagulant (trade name, Union Carbide) WSR 303 (trade name, manufactured by Union Carbide Co.) (viscosity of 1% by weight aqueous solution at 25 ° C .: 750 to 10,000 mPa · s), WSR Polyethylene oxide such as 308 (trade name, manufactured by Union Carbide Co.) (viscosity of 1% by weight aqueous solution at 25 ° C .: 10,000 to 15,000 mPa · s);
Sunrose F-150MC (trade name, manufactured by Nippon Paper Industries) (viscosity of 1% by weight aqueous solution at 25 ° C: 1200 to 1800 mPa · s), Sunrose F-300MC (tradename, manufactured by Nippon Paper Industries) (at 25 ° C) Sodium carboxymethylcellulose such as 1% by weight aqueous solution viscosity: 2500-3000mPa · s), Sunrose F-1000MC (trade name, manufactured by Nippon Paper Industries) (viscosity of 1% by weight aqueous solution at 25 ° C: 8000-12000mPa · s) ;
LH-11 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-21 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-31 (trade name, Shin-Etsu Chemical Co., Ltd.), LH- 22 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-32 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-20 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-30 ( Low-substituted hydroxypropylcellulose such as trade name, manufactured by Shin-Etsu Chemical Co., Ltd.). These hydrophilic polymers may be used as a mixture of two or more kinds at an appropriate ratio.

The content of the physiologically active substance in the controlled release composition of the present invention varies depending on the type of the physiologically active substance, the size of the preparation, etc., for example, 1 to 90% by weight, preferably 5 to 85% by weight, more preferably 10% by weight. 8080% by weight.
The content of the hydrophilic polymer in the controlled release composition of the present invention varies depending on the content of the physiologically active substance, the size of the preparation, the type of the hydrophilic polymer, and the like, for example, 3 to 95% by weight, preferably It is 5 to 95% by weight, more preferably 5 to 90% by weight.

The above-mentioned controlled release composition has the above-mentioned physiologically active substance and hydrophilic polymer at the above-mentioned contents, respectively, and thereby has an acidic pH (e.g., pH 1-3) corresponding to elution near the stomach at the initial stage after oral administration. The elution of the physiologically active substance is suppressed immediately after, and the elution of the physiologically active substance is continued for a long time after the small intestine, especially in the weakly acidic to weakly alkaline conditions (e.g., pH 5 to 8) corresponding to the elution in the small to small intestine. Will be sustained.
Specifically, in the above controlled release composition,
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid, 900 mL dissolution test method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C), a controlled release composition 15 minutes after the start of the test. The elution rate of the physiologically active substance from is less than 40%,
2) In the Japanese Pharmacopoeia disintegration test, 900 mL of the second liquid dissolution test using 900 mL of the second solution (paddle method, paddle rotation speed 50 rpm, 37 ° C), controlled release composition 24 hours after the start of the test The elution rate of the physiologically active substance from is not less than 40%.

  The dosage form of the above-mentioned controlled release composition may be in any form suitable for oral administration such as tablets, granules, fine granules, pellets, capsules, crystals, pastes and the like. Among them, tablets, capsules, granules and the like are preferable.

  The above-mentioned controlled release composition can be produced by mixing the above-mentioned physiologically active substance and the hydrophilic polymer at the above-mentioned contents, respectively, and molding the mixture. Here, mixing and molding can be performed according to a method commonly used in the field of pharmaceutical technology. The dispersion mode of the physiologically active substance in the molded product may be uniform dispersion or non-uniform dispersion, but uniform dispersion is desirable.

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である生理活性物質、(2)ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、カルボキシメチルセルロースナトリウムおよび低置換度ヒドロキシプロピルセルロースから選ばれる親水性高分子および(3)ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる滑沢剤を含有して構成される。 In mixing and / or molding, a pharmacologically acceptable carrier may be used. Here, the "pharmacologically acceptable carrier" includes various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
Preferred examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan , Light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate, and the like.
Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate, and magnesium aluminate metasilicate.
Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, acacia, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, and hydroxy. Propylmethylcellulose, polyvinylpyrrolidone and the like.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose and the like.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of the antioxidant include sulfite, ascorbate and the like.
Preferred examples of the coloring agent include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5 and edible blues 1 and 2), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, β-carotene, chlorophyll, and red iron oxide).
Preferred examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
Specifically, preferred of the above controlled release compositions are those represented by formula (1):

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent.) Or a salt thereof, a physiologically active substance, (2) hydroxypropylcellulose, Hydrophilic polymers selected from hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, and (3) magnesium stearate, calcium stearate, talc, light silicic anhydride, colloidal silica, synthetic silicic acid It is configured to contain a lubricant selected from aluminum and magnesium aluminate metasilicate.

The physiologically active substance contained in the above-mentioned controlled release composition is weakly acidic to weakly alkaline and has relatively low water solubility, and when used as a preparation for oral administration, dissolution and absorption of the physiologically active substance from the small intestine and beyond are not possible. If there is a possibility that it will be sufficient, a pH adjuster or other solubilizer may be added for the purpose of adjusting the dissolution behavior from the composition. By using a pH adjuster or the like, it is possible to reduce a change in drug dissolution due to environmental pH. In addition, since individual patients may have different in-vivo pH, reducing the change in drug dissolution due to environmental pH is extremely significant in order to obtain uniform drug efficacy for various patients.
Examples of the pH adjuster include organic acids such as citric acid, tartaric acid, adipic acid, ascorbic acid, malic acid, fumaric acid, malonic acid, succinic acid, maleic acid, aspartic acid, and glutamic acid and salts thereof (for example, dicitrate). Sodium hydrogen hydride, disodium citrate, calcium citrate, monosodium fumarate, monosodium succinate, sodium aspartate, magnesium aspartate, arginine glutamate, potassium glutamate, sodium glutamate), inorganic acids such as phosphoric acid, hydrochloric acid, and sulfuric acid Examples include acids and salts thereof (eg, potassium dihydrogen phosphate, sodium dihydrogen phosphate, etc.), and acidic polymers such as carboxyvinyl polymers and salts thereof. Among them, citric acid, tartaric acid, fumaric acid, ascorbic acid, aspartic acid, glutamic acid and salts thereof are preferred. As other solubilizers, for example, β-cyclodextrin, cyclodextrins such as maltosyl-β-cyclodextrin, surfactants such as polysorbate 80 and glyceryl monostearate, polyethylene glycol 4000 and polyethylene glycol Polyethylene glycol such as 6000.
The content of the pH adjuster or other solubilizing agent varies depending on the type and content of the physiologically active substance, the size of the composition, and the like, but is, for example, 1 to 50% by weight, preferably 5 to 40% by weight.

  When the above-mentioned controlled release composition is a granule, for example, the above-mentioned physiologically active substance is sprayed onto the inert carrier particles while spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.). Rolling granulation method, pan coating method, fluidized bed by adding a substance and a hydrophilic polymer, or a mixture of these and excipients, lubricants, etc. in small amounts as a solution or suspension as a spray or powder It can also be prepared by a coating method, a melt granulation method, an extrusion malm method, or the like. As the inert carrier particles, those produced from, for example, sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable.

  When the above-mentioned controlled release composition is a tablet, a hydrophilic polymer or the above-mentioned excipient, disintegrant, binder or lubricant is added to the physiologically active substance and mixed (if necessary, further kneading is performed). ), And can be prepared by compression molding.

Since the above-mentioned controlled release composition has low toxicity and few side effects, it is safely orally administered to mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, etc., particularly humans). In particular, it can be used as a therapeutic or preventive agent for the above-mentioned various diseases, preferably prostate cancer, breast cancer, etc., which can provide a preventive / therapeutic effect by inhibiting steroid C _17,20 lyase.

  The dose of the above-mentioned controlled-release composition varies depending on the type of the physiologically active substance, the administration subject, the number of administrations, and the like. For example, one dose when orally administered to an adult solid tumor patient (for example, a prostate cancer patient) is used. The daily dose is usually about 0.001 to about 500 mg / kg body weight, preferably about 0.01 to about 40 mg / kg body weight, more preferably about 0.1 to about 20 mg / kg body weight, as an effective amount of the physiologically active substance. is there.

  The effect of the above-mentioned controlled release composition can be further enhanced by using it in combination with another physiologically active substance having a medicinal effect. Examples of other physiologically active substances having a medicinal effect include “sex hormonal agents (hormonal drugs)”, “alkylating agents”, “antimetabolites”, “anticancer antibiotics”, “plant alkaloids”, “immune Therapeutic agents "," agents inhibiting the action of cell growth factors and their receptors "and the like (hereinafter abbreviated as concomitant drugs). The concomitant drug can be used as another pharmaceutical composition, or can be prepared as a mixture by including it in the above-mentioned controlled release composition.

  Examples of the "sex hormone agent" include, for example, phosphestrol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, guestrinone, meparttricin , Raloxifene, olmeloxifene, revolmeloxifene, antiestrogen (eg, tamoxifen citrate, toremifene citrate, etc.), pill preparation, mepithiostan, test lactone, aminoglutethimide, LHRH receptor modulator [LH-RH Receptor agonists (eg, goserelin acetate, buserelin acetate, leuprorelin acetate, etc.), LH-RH receptor antagonists (eg, ganirelix, cetrorelix, abarelix, etc.)], droloxifene, epiti Stanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozol, formestane, etc.), antiandrogen (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibition Drugs (eg, finasteride, epristeride, etc.), corticosteroids (eg, cortisol, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, abiraterone, etc.), drugs that delay the metabolism of retinoids and retinoids ( For example, liarosole) and the like.

  Examples of the "alkylating agent" include, for example, nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mercuron Phalan, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemus Prednimustine, bumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zino Tati Nsu Chima Lamar, adozelesin, system scan Chin, Bizereshin, and the like.

  Examples of "antimetabolites" include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine octophosphate, ancitabine hydrochloride, 5-FU drugs (for example, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, emitefur, etc.), aminopterin, leucovorin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxyuridine, mitofazone, thiazoline, azofurin, etc. No.

  As the `` anticancer antibiotic '', for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocarzinostatin, mythramycin, sarcomycin, carcinophilin, mitotane, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like.

  Examples of the "plant alkaloid" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, vinorelbine and the like.

  Examples of the `` immunotherapeutic agent (BRM) '' include, for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium Umpartum, levamisole, polysaccharide K, procodazole and the like.

  The "cell growth factor" in the "drug that inhibits the action of the cell growth factor and its receptor" may be any substance that promotes cell growth, and is usually a peptide having a molecular weight of 20,000 or less. In, a factor whose action is exerted at a low concentration by binding to a receptor, specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity as that (e.g., EGF , Heregulin (HER2 ligand) etc.], (2) insulin or a substance having substantially the same activity as that [eg, insulin, IGF (insulin-like growth factor) -1, IGF-2 etc.), (3) FGF (fibroblast growth factor) or a substance having substantially the same activity as that (eg, acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, etc.), (4) other cell growth factors (eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interl eukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), and the like.

  The “cell growth factor receptor” may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factor. Specifically, EGF receptor, HER2 (heregulin receptor), Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2 and the like.

  “Agents that inhibit the action of cell growth factors” include cell growth factors such as cetuximab and other EGF receptor antibodies, herceptin and other HER2 antibodies and antibodies to their receptors, Iressa (EGF receptor tyrosine kinase) Tyrosine kinase inhibitors such as GW2016 (EGF receptor / HER2 tyrosine kinase inhibitor), compounds described in WO98-03505A pamphlet and WO01-77107A pamphlet (HER2 tyrosine kinase inhibitor), and cell growth factors and their receptors Ribozymes, antisense drugs, and the like, which suppress the expression of ribozymes.

  In addition to the above drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex, mercury hematoporphyrin sodium, topoisomerase I inhibitor (eg, irinotecan, topotecan, etc.), topoisomerase II inhibitor (eg, sobuzoxane, etc.) ), Differentiation inducers (eg, retinoids, vitamin Ds, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride, etc.) and the like can also be used.

  The concomitant drug is preferably an LHRH receptor modulator (LHRH modulator) [eg, an LHRH receptor agonist (eg, goserelin acetate, buserelin acetate, leuprorelin acetate, etc.) or an LHRH receptor antagonist (eg, ganirelix, cetrorelix, abarelix, etc.) )], And by using them together, it is possible to more effectively remove androgen or estrogen in blood.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the physiologically active substance and the concomitant drug in the controlled release composition of the present invention can be appropriately selected depending on the administration subject, target disease, symptoms, combination, and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the above-mentioned physiologically active substance.

  The present invention also covers a core containing a compound represented by the above formula (I) -A or a salt thereof or a prodrug thereof as a physiologically active substance with a coating layer containing a polymer, that is, a release controlling film. (Hereinafter sometimes abbreviated as “membrane-coated type controlled release composition”). However, no physiologically active substance (including a substance different from the physiologically active substance contained in the nucleus) is contained in the coating layer. Here, the “bioactive substance” refers to a substance contained to achieve a desired medicinal effect, and does not include a substance to be added as a pharmaceutical additive such as an excipient.

  The polymer contained in the coating layer (hereinafter, also referred to as “coating polymer” in this specification) is a pharmacologically acceptable polymer and releases a physiologically active substance contained in the nucleus. There is no particular limitation as long as a film structure having a controlling function can be formed. There is no particular limitation on the type of the release control membrane.For example, 1) those having relatively large micropores such as a porous membrane and controlling the release of inclusions through the micropores, 2) film-like nonporous Examples of the membrane include those that control the release of inclusions by diffusion through molecular chain gaps due to the molecular motion of the film-forming polymer, and 3) those that control the release of inclusions as the membrane dissolves and decomposes. In the case of the above 1) and 2), as the coating polymer, for example, a water-insoluble or poorly water-soluble polymer, and in the case of 3), for example, exhibits a pH-dependent or dissolution-deteriorated water-soluble property. A polymer or the like can be used.

  Polymers that exhibit pH-dependent water solubility are, for example, insoluble or poorly soluble in acidic (pH 1-3) media such as gastric juice, and weakly acidic to weakly alkaline (pH 5-8) such as intestinal fluid. A polymer having an acidic dissociating group, which is soluble in a medium in any pH range, is preferred. Examples of such a polymer exhibiting pH-dependent water solubility include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer (methacrylic acid-methyl acrylate) used as an enteric coating agent. Copolymers, methacrylic acid-ethyl acrylate copolymer, and the like, for example, Eudragit L100-55, L30D-55, L100, S100, FS (trade name, Rohm Pharma Co., Ltd.) and the like. These polymers may be used as a mixture of two or more kinds at an appropriate ratio.

As a specific example of the polymer exhibiting water solubility of the dissolution delay type, a specific example of the polymer includes HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: 2.0-2.9 mPa · s), HPC-SL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 3.0-5.9 mPa · s), HPC-L (trade name, Nippon Soda) (Viscosity of a 2% by weight aqueous solution at 20 ° C: 6.0 to 10.0 mPa · s), HPC-M (trade name, manufactured by Nippon Soda Co., Ltd.) (Viscosity of a 2% by weight aqueous solution at 20 ° C: 150) Hydroxypropyl cellulose (HPC) such as HPC-H (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 1000 to 4000 mPa · s);
TC-5E (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 3 mPa · s), TC-5EW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C.) Of a 2% by weight aqueous solution at about: 3 mPa · s), SB-4 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 4 mPa · s), TC-5MW ( Brand name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4.5 mPa · s) TC-5R (brand name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2% by weight at 20 ° C.) Viscosity of aqueous solution: about 6 mPa · s), TC-5RW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 6 mPa · s), TC-5S (trade name, Shin-Etsu) (Manufactured by Chemical Industry Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 15 mPa · s), Metrolose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C.) : About 50mPa ・ s), Metro 6565SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 50 mPa · s); Metrolose 90SH-100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) Viscosity of a 2% by weight aqueous solution at 20 ° C .: about 100 mPa · s), Metrolose 65SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metrolze 90SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metroz 65SH-1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 Viscosity of 2% by weight aqueous solution at ℃: about 1500 mPa · s), Metrolose 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% by weight aqueous solution at 20 ° C: about 4000 mPa · s), Metrolse 65SH -4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metroze 90SH-4 000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of a 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose 90SH-30000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (at 20 ° C.) Viscosity of a 2% by weight aqueous solution: about 30 000 mPa · s) such as hydroxypropyl methylcellulose;
Metrolose SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity: about 15 mPa · s, 2% by weight aqueous solution, 20 ° C), Metrolose SM25 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 at 20 ° C) Viscosity of aqueous solution by weight: about 25 mPa · s), Metrolose SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 100 mPa · s), Metrolose SM400 (brand name, Shin-Etsu) (Manufactured by Chemical Industry Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 400 mPa · s), Metrolose SM1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 1500 mPa · s), Metrolose SM4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: about 4000 mPa · s), Metrolose SM8000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of a 2% by weight aqueous solution at 20 ° C .: about 8000 mPa · s);
WSR N-12K (trade name, manufactured by Union Carbide Co.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 400 to 800 mPa · s), WSR N-60K (trade name, manufactured by Union Carbide Co.) (2 weight at 20 ° C.) % Aqueous solution: 2000-4000 mPa · s), WSR 301 (trade name, manufactured by Union Carbide) (viscosity of 1% by weight aqueous solution at 25 ° C .: 1500-4500 mPa · s), WSR Coagulant (trade name, Union Carbide) WSR 303 (trade name, manufactured by Union Carbide Co.) (viscosity of 1% by weight aqueous solution at 25 ° C .: 750 to 10,000 mPa · s), WSR Polyethylene oxide such as 308 (trade name, manufactured by Union Carbide Co.) (viscosity of 1% by weight aqueous solution at 25 ° C .: 10,000 to 15,000 mPa · s);
Sunrose F-150MC (trade name, manufactured by Nippon Paper Industries) (viscosity of 1% by weight aqueous solution at 25 ° C: 1200 to 1800 mPa · s), Sunrose F-300MC (tradename, manufactured by Nippon Paper Industries) (at 25 ° C) Sodium carboxymethylcellulose such as 1% by weight aqueous solution viscosity: 2500-3000mPa · s), Sunrose F-1000MC (trade name, manufactured by Nippon Paper Industries) (viscosity of 1% by weight aqueous solution at 25 ° C: 8000-12000mPa · s) ;
LH-11 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-21 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-31 (trade name, Shin-Etsu Chemical Co., Ltd.), LH- 22 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-32 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-20 (trade name, Shin-Etsu Chemical Co., Ltd.), LH-30 ( Low-substituted hydroxypropylcellulose such as trade name, manufactured by Shin-Etsu Chemical Co., Ltd.). Preferably, it is a polymer having a viscosity of a 2% by weight aqueous solution at 20 ° C. or a 1% by weight aqueous solution at 25 ° C. of 10 mPa · s or more. These polymers may be used as a mixture of two or more kinds at an appropriate ratio.

  The water-insoluble or poorly water-soluble polymer includes block polymers and copolymers. The water-insoluble or poorly water-soluble polymer refers to a polymer having a water solubility of less than 0.1 mg / mL at 37 ° C. For example, carnauba wax, hardened castor oil, hardened rapeseed oil, fat-soluble bases such as polyglycerin; cellulose ester, acrylic polymer, polyvinyl acetate, polyvinyl chloride, a composition wherein at least one of the components is selected from the above polymers, or And the like. For example, polyvinyl acetate, polymethyl methacrylate, poly (vinyl chloride, vinyl alcohol, vinyl acetate) (terpolymer of vinyl chloride, vinyl alcohol and vinyl acetate) and the like. Also, for example, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose, polymethyl methacrylate, poly (ethyl acrylate, methyl methacrylate), such as Eudragit NE (trade name, ROHM PHARMA), polyethylene , Polyisobutylene, poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), such as Eudragit RS, RL (trade name, Rohm Pharma Co.), a composition wherein at least one of the components is selected from the above polymers, Or a mixture thereof, but is not limited thereto. Commercially available latex, pseudolatex and polymer emulsions can also be used for coating.

In one preferred embodiment of the invention, the coating polymer is a methacrylic acid-methyl acrylate copolymer or a methacrylic acid-ethyl acrylate copolymer.
In another preferred embodiment, the coating polymer is poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride).

  A plasticizer may be added to the coated polymer to adjust the softening temperature of the polymer. Softening temperature is an important factor for controlling the mechanical properties of a polymer. Examples of suitable plasticizers include acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin, citrate But not limited thereto.

The core containing a physiologically active substance can be produced based on a conventional method known in the field of pharmaceutical technology. The core can take the form of, but not limited to, tablets, granules, fine granules, pellets, capsules, crystals, pastes, liquids, and the like.
The release of the physiologically active substance from the nucleus may be immediate release in the absence of the coating layer, or may be sustained release. Here, “immediate release” refers to the start of the test when the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) is carried out using 900 mL of an appropriate test solution at a paddle speed of 50 rpm. The dissolution rate of the drug from the composition after 80 minutes is 80% or more. When performed under rpm conditions, the drug dissolution rate from the composition 30 minutes after the start of the test is 80% or more, and `` sustained release '' refers to the Japanese Pharmacopoeia under the same conditions as described above. Dissolution test method When the second method (paddle method) or the first method (rotating basket method) is performed, the dissolution rate of the drug from the preparation 30 minutes after the start of the test is less than 80%. As the test liquid, those commonly used in the technical field of pharmaceutical preparations, for example, water, buffer, and the like are used.

The release mechanism of the physiologically active substance from the nucleus in the absence of the coating layer is not particularly limited. That release a bioactive substance in response to changes in the environment, those that release the bioactive substance by its internal pressure when the inside of the nucleus expands by taking in environmental moisture, those that release the bioactive substance immediately by disintegration or dissolution, etc. Any of these may be used.
Here, the “composition in which the physiologically active substance is released from the composition by passive diffusion” includes, for example, a matrix composition using the above-mentioned hydrophilic polymer (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, etc.). , A matrix composition using a fat-soluble base (eg, carnauba wax, hardened castor oil, hardened rapeseed oil, polyglycerin fatty acid ester, etc.), and other release controlling bases (eg, cellulose-based polymers such as ethyl cellulose; A matrix composition using an aminoalkyl methacrylate copolymer RS, an ethyl acrylate-methyl methacrylate copolymer suspension [acrylic acid polymer such as Eudragit NE], and the like.
Examples of the “composition that releases a physiologically active substance upon erosion of the preparation” include capsules containing polyglycolized glyceride (eg, Gelucire50 / 13 (trade name, manufactured by GATTEFOSSE)).
Examples of the “composition that releases a physiologically active substance in response to a change in environmental pH” include, for example, an enteric base (eg, methacrylic acid copolymer L [Eudragit L (trade name, manufactured by Rohm Pharma Co.)), Matrix composition using acrylic copolymer such as acid copolymer LD (Eudragit L-30D55 (trade name, manufactured by Rohm Pharma)) and methacrylic acid copolymer S (Eudragit S (trade name, manufactured by Rohm Pharma)) Things.
Examples of the “composition that expands the inside of the composition by taking in environmental moisture and releases a physiologically active substance at the internal pressure” include, for example, an OROS (OROS) system (trade name, manufactured by Alza).
Examples of the “composition that is immediately released by disintegration or dissolution (immediate release composition)” include a composition obtained by mixing a physiologically active substance and a pharmacologically acceptable carrier and molding the mixture. Can be Here, as the pharmacologically acceptable carrier, the same as described above can be mentioned. In addition, mixing and molding are performed according to a method commonly used in the field of pharmaceutical technology. The form of dispersion of the physiologically active substance in the molded product may be uniform dispersion or non-uniform dispersion, but uniform dispersion is desirable. As a release mechanism of the physiologically active substance, it is preferable that the substance is immediately released by disintegration or dissolution, that is, a rapid release.

A nucleus containing a physiologically active substance can be prepared by dispersing or dissolving in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on inert carrier particles serving as the core of the nucleus, in addition to the above-mentioned production method. Molecules (eg, hydroxypropylcellulose (eg, HPC-SL etc.), hydroxypropylmethylcellulose (eg, TC-5-RW, TC-5-EW etc.), low-substituted hydroxypropylcellulose (eg, L-HPC-32) ), Etc.) while spraying a small amount of a mixture of a physiologically active substance or a mixture thereof with excipients (eg, mannitol, crystalline cellulose, etc.), lubricants (eg, talc, light silicic anhydride, etc.) Alternatively, it can be used as a tumbling granulation method, a pan coating method, a fluidized bed coating method, a melt granulation method, an extrusion malm method, etc., which are performed by adding a suspension as a spray or powder. It can also be prepared me. As the inert carrier particles, those produced from, for example, sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 50 μm to about 1,500 μm are preferable.
Alternatively, for example, the above-mentioned excipient, disintegrant, binder or lubricant is added to the physiologically active substance, mixed (if necessary, further kneaded), and compression molded to prepare a tablet. You can also.

  When the physiologically active substance is weakly acidic to weakly alkaline and has relatively low water solubility, for the purpose of adjusting the dissolution behavior from the composition, even if a pH adjuster or other solubilizing agent is added as described above. Good.

  When the release of the physiologically active substance from the nucleus in the absence of the coating layer is sustained release, preferably, the matrix composition containing the above-mentioned physiologically active substance and a hydrophilic polymer is directly applied as the nucleus. be able to.

The physiologically active substance content in the nucleus varies depending on the type of the physiologically active substance, the size of the nucleus, etc., for example, 1% by weight to 90% by weight, preferably 5% by weight to 85% by weight, more preferably 10% by weight to 80% by weight.
When the core is granules or fine granules, the average particle size is preferably about 50 to 2000 μm, more preferably about 100 to about 1400 μm.
When the nucleus is a controlled release matrix composition containing a hydrophilic polymer, the content of the hydrophilic polymer in the nucleus varies depending on the content of the physiologically active substance, the size of the nucleus, the type of the hydrophilic polymer, and the like. For example, 3% to 95% by weight, preferably 5% to 95% by weight, more preferably 10% to 90% by weight.

The film-coated controlled release composition of the present invention can take the form of tablets, granules, pellets, or the like depending on the form of the core, or may be a capsule containing them, but is not limited thereto. Not done.
The film-coated type controlled release composition of the present invention is obtained by coating the core obtained as described above with an aqueous dispersion or non-aqueous solution of a coating polymer (hereinafter, also referred to as “coating liquid”) and drying. It is manufactured by Alternatively, for example, it is also manufactured by compression-molding the coated polymer around the core to form a coating layer using a method commonly used in the field of pharmaceutical preparations similar to the case of preparing a multilayer tablet or a dry coated tablet. You.
Examples of the method of coating the core with the coating liquid include a method of spray coating.
The amount of the coating layer after drying is about 0.01% to about 500% by weight, preferably about 0.1% to about 300% by weight, more preferably about 1% to about 200% by weight, based on the core.
The coating layer has a thickness of about 1 μm to about 10 mm, preferably about 5 μm to about 5 mm.

As the solvent for the coating liquid, water or an organic solvent can be used alone or a mixture of both. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%. The organic solvent is not particularly limited as long as it dissolves the coating polymer, but the above-mentioned ones are preferably used. However, water or a mixture of water and an organic solvent is more preferably used. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating solution as a stabilizer.
The operation in the case of coating by spray coating can be carried out by a usual coating method.Specifically, it can be carried out by spray-coating the coating liquid onto the core by, for example, a fluidized bed coating method or a pan coating method. it can. At this time, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light silicic anhydride, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. are plasticized. It may be added as an agent.
After coating, if necessary, an antistatic agent such as talc or light anhydrous silicic acid may be mixed.

  One or more ionic, nonionic, or polymeric surfactants may be added to the coating solution as a stabilizer. Examples of suitable surfactants include diethanolamine, fatty acids, hydroxypropylmethylcellulose, hydroxypropylcellulose, monoethanolamine, nonoxynol, octoxynol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyoxy fatty acid, polyoxyl hydrocarbon ether , Polysorbate (eg, polysorbate 80, etc.), povidone, fatty acid salt, sodium lauryl sulfate, sorbitan ester, trolamine and the like, but are not limited thereto.

（式中、nは1ないし3の整数、Arは置換基を有していてもよい芳香環を示す。）で表される化合物もしくはその塩である生理活性物質および(2)ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、ポリエチレンオキシド、カルボキシメチルセルロースナトリウムおよび低置換度ヒドロキシプロピルセルロースから選ばれる親水性高分子を含有する核を、(B)(1)セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネートおよびメタクリル酸コポリマーから選ばれる腸溶コーティング剤、(2)ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる滑沢剤および(3)クエン酸アセチルトリブチル、クエン酸アセチルトリエチル、ヒマシ油、ジアセチル化モノグリセリド、セバシン酸ジブチル、フタル酸ジエチル、グリセリン、モノ及びジアセチル化モノグリセリド、ポリエチレングリコール、プロピレングリコール、トリアセチンおよびクエン酸トリエチルから選ばれる可塑剤を含有する被覆層で被覆してなる放出制御組成物である。 The membrane-coated controlled release composition of the present invention is equivalent to elution near the stomach in the early stage after oral administration by coating the core containing the above-mentioned physiologically active substance with the above-mentioned polymer using the above-mentioned method. Immediate elution of a physiologically active substance at an acidic pH (e.g., pH 1 to 3) is suppressed, and weak acidity to weak alkalinity (e.g., pH 5 to 8) corresponding to the subsequent elution from the small intestine, particularly from the upper small intestine to the lower small intestine. In), the elution of the physiologically active substance is maintained for a long time. In particular, the use of a controlled release membrane makes it possible to more strictly control the elution in the early stage after administration.
Specifically, in the film-coated release controlled composition of the present invention,
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid, 900 mL dissolution test method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C), a controlled release composition 15 minutes after the start of the test. The elution rate of the physiologically active substance from is less than 10%,
2) Release control composition 24 hours after the start of the test in the Japanese Pharmacopoeia dissolution test method 2 using 900 mL of the second liquid of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed 50 rpm, 37 ° C) The elution rate of the physiologically active substance from the substance is 40% or more.
Specifically, the film-coated controlled-release composition of the present invention is represented by the formula (A) (1):

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a physiologically active substance which is a salt thereof, and (2) hydroxypropylcellulose, Hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, carboxymethylcellulose sodium and a nucleus containing a hydrophilic polymer selected from low-substituted hydroxypropylcellulose, (B) (1) cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate Enteric coating agent selected from succinate and methacrylic acid copolymers, (2) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate and methacrylic acid A lubricant selected from magnesium acid aluminate and (3) acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglyceride, polyethylene glycol, It is a controlled release composition coated with a coating layer containing a plasticizer selected from propylene glycol, triacetin and triethyl citrate.

  The controlled release composition of the present invention includes (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl 2-naphthamide or a salt thereof, (2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, hydrophilic polymer selected from sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, (3) lactose, sucrose, starch Disintegrants selected from carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted hydroxypropylcellulose, (4) magnesium stearate, calcium stearate, talc, light anhydrous silica Acid, colloidal silica, Lubricants selected from aluminum silicate and magnesium metasilicate aluminate, (5) cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (6) α Binder selected from activated starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone And (7) acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetyl Preferred specific examples include a controlled release composition comprising a plasticizer selected from monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin and triethyl citrate. . Also, (A) (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or A core comprising a salt thereof and a hydrophilic polymer selected from (2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, carboxymethylcellulose sodium and low-substituted hydroxypropylcellulose, (B) (1) Enteric coating agent selected from cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (2) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate And aluminum metasilicate Lubricants selected from magnesium silicate and (3) acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol Controlled release compositions coated with a coating agent containing a plasticizer selected from triacetin and triethyl citrate are also preferred examples.

Since the membrane-coated controlled release composition has low toxicity and few side effects, it can be safely orally administered to mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, etc., especially humans). It can be administered, and it can be used as a therapeutic or preventive drug for the above-mentioned various diseases, preferably prostate cancer, breast cancer and the like, which can provide a preventive / therapeutic effect by inhibiting steroid C _17,20 lyase.
The dose of the membrane-coated controlled release composition varies depending on the type of the physiologically active substance, the subject to be administered, the number of times of administration, and the like. For example, when administered orally to an adult solid tumor patient (for example, a prostate cancer patient) The daily dose is usually about 0.001 to about 500 mg / kg body weight, preferably about 0.1 to about 40 mg / kg body weight, more preferably about 0.5 to about 20 mg / kg body weight as the effective amount of the physiologically active substance. It is.

The effect of the film-coated controlled release composition can be further enhanced by using it in combination with a physiologically active substance having another medicinal effect. Preferred examples of the physiologically active substance having other medicinal properties include the same as the above-mentioned concomitant drugs. The concomitant drug can be used as another pharmaceutical composition, or can be prepared as a mixture by including it in the above-mentioned controlled release composition.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the mixing ratio of the physiologically active substance and the concomitant drug in the controlled release composition of the present invention can be appropriately selected depending on the administration subject, target disease, symptoms, combination, and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the above-mentioned physiologically active substance.

The above-described controlled release composition of the present invention (naked matrix composition) and membrane-coated controlled release composition (hereinafter, collectively referred to as “controlled release composition of the present invention”) are used to release a physiologically active substance. It can be coated with a coating layer that has immediate release properties. The bioactive substance may be the same as or different from the bioactive substance contained in the controlled release composition of the present invention. If different, the above-mentioned concomitant drugs are preferably exemplified as the physiologically active substance.
With such a configuration, the controlled release composition of the present invention can be imparted with rapid drug dissolution in the early stage after oral administration.

  The controlled release composition of the present invention may be used in combination with one or more other controlled release compositions, in which case it may be a single agent or a plurality of agents independent of each other. It may be. Here, examples of the single agent include a single capsule enclosing two or more controlled release compositions, a multilayer tablet having a plurality of controlled release portions, and the like.

The physiologically active substance contained in another controlled release composition and whose release is controlled may be the same as or different from any of the compounds described above contained in the controlled release composition of the present invention. Is also good.
When the physiologically active substance contained in the other controlled release composition is different from the physiologically active substance contained in the controlled release composition of the present invention, an additive or a synergistic effect of the medicinal effect or a side effect reduction of the side effect or the like is required. Agents are preferred. Combination of bioactive substances that have the same or different action sites, but exhibit the same efficacy, or inactivator is inhibited by another bioactive substance to maintain the blood stability of the bioactive substance , A competitive combination, or a combination in which a metabolic factor is inhibited by another physiologically active substance in order to avoid or delay the metabolism of the physiologically active substance.
Further, the release of the physiologically active substance contained in another controlled release composition stabilizes the physiologically active substance contained in the controlled release composition of the present invention in the digestive tract, optimizes the dissolution rate, and improves the absorption rate. A combination that expects the above is also preferable.

Preferably, the physiologically active substance contained in the other controlled release composition has high water solubility under acidic conditions. Specifically, the solubility (one solution at 37 ° C.) has a solubility of about 0.1 mg. / mL or more, preferably about 0.5 mg / mL or more, more preferably about 1 mg / mL or more.
More preferably, the physiologically active substance contained in the other controlled release composition is the same substance as the physiologically active substance contained in the controlled release composition of the present invention, that is, represented by the above formula (I) -A. Or a salt thereof.

As described above, the controlled release composition of the present invention suppresses the immediate elution of a physiologically active substance at an acidic pH (e.g., pH 1 to 3) corresponding to the elution near the stomach at the early stage after oral administration, and further suppresses the Since then, the elution of the physiologically active substance has been continued for a long time especially in the weakly acidic to weakly alkaline (e.g., pH 5 to 8) corresponding to the elution in the upper to lower intestines. Therefore, when the other controlled release composition contains the same substance as the physiologically active substance contained in the controlled release composition of the present invention, the other controlled release composition may be, for example, an immediate release around the stomach to the duodenum. Uniform drug release / drug in the gastrointestinal tract by using a rapid release composition for realizing dissolution and / or a timed release controlled release composition for improving dissolution near the large intestine Absorption can be achieved.
That is, the present invention comprising a combination of the controlled release composition of the present invention and one or more other controlled release compositions containing the same bioactive substance as the bioactive substance contained in the controlled release composition of the present invention. The composition of the present invention (hereinafter, also referred to as “mixed release controlled composition of the present invention”) has the following dissolution characteristics.
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid dissolution test using 900 mL of the first solution (Paddle method, paddle rotation speed 50 rpm, 37 ° C), controlled release composition 15 minutes after the start of the test The dissolution rate of the physiologically active substance from the substance is less than 10%. , 37 ° C.), the release rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 20% or more. The mixed controlled release composition of the present invention has at least one other controlled release composition. The release rate and release timing of the physiologically active substance in the object may be different. For example, a time-controlled release controlled-release composition using a controlled-release film or the like, which includes a case where the physiologically active substance in the nucleus is eluted immediately after the film is disintegrated or dissolved. Therefore, the other controlled release composition, even if the core containing a physiologically active substance is coated with a coating layer containing a polymer exhibiting pH-dependent or dissolution-delayed water-soluble polymer. Good. As the pH-dependent or delayed-solution type polymer exhibiting water solubility, the same polymers as described above can be preferably used. For example, Eudragit L-100, S-100, FS (trade name, Rohm Pharma Co., Ltd.) Company).

Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Comparative Examples, Examples, and Experimental Examples. However, these are merely examples, and do not limit the scope of the present invention in any way.
In the following Reference Examples, Comparative Examples and Examples, (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-7- Yl) -N-methyl-2-naphthamide (hereinafter referred to as compound A) was used.
Further, as hydroxypropylcellulose, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol 6000, red iron sesquioxide, and titanium oxide, products conforming to the 14th revised Japanese Pharmacopoeia were used.

Comparative Example 1
Compound A, D-mannitol, low-substituted hydroxypropylcellulose (L-HPC-11), hydroxypropylcellulose (HPC-L), magnesium stearate, hydroxypropylmethylcellulose 2910 (TC-5), polyethylene glycol 8000, titanium oxide Powdered iron sesquioxide was mixed in the following amounts, and about 300 mg of each powder was weighed and tableted to give immediate-release tablets (comparative preparation 1) having a diameter of about 10 mm and containing 100 mg of compound A.
Compound A 100 mg
D-mannitol 133.5 mg
Low-substituted hydroxypropylcellulose 42 mg
Hydroxypropyl cellulose 6.5 mg
Magnesium stearate 3 mg
Hydroxypropyl methylcellulose 2910 10.416 mg
Polyethylene glycol 8000 2.1 mg
1.4 mg titanium oxide
Ferric oxide 0.084 mg

Example 1
Compound A of about 3.2 g, hydroxypropylmethylcellulose (TC-5MW) about 6.4 g and magnesium stearate from about 96 mg after mixing, were weighed by about 303 mg, a diameter of 9mm in tabletting pressure 2.5 ton / cm ^2, 7.5 Tablets were formed into an R shape (formulation 1).

Example 2
About 3.2 g of Compound A, about 1.28 g of polyethylene oxide polymer (Polyox COAG), about 5.12 g of polyethylene glycol (PEG6000) and about 96 mg of magnesium stearate were powder mixed, and about 303 mg each was weighed, and a tableting pressure of 2.5 The tablets were tableted at ton / cm ² into a shape having a diameter of 9 mm and 7.5R (Formulation 2).

Example 3
About 3.2 g of Compound A, about 1.28 g of hydroxypropyl methylcellulose (Metroose 90SH-4000), about 5.12 g of polyethylene glycol (PEG6000) and about 96 mg of magnesium stearate are powder-mixed, and about 303 mg are weighed, and the tableting pressure is measured. It was tableted at 2.5 ton / cm ² into a shape of 9R in diameter and 7.5R (Formulation 3).

Example 4
The tablets obtained in Comparative Example 1 and Examples 1 to 3 were coated as follows.
About 4 g of polyethylene glycol 6000 as a plasticizer and about 1.4 g of polysorbate 80 were dissolved in about 236 g of purified water, and about 12 g of talc as a lubricant was uniformly dispersed. About 144 g of Eudragit L-30D-55 (trade name), which is a solution of the methacrylic acid copolymer, was added to this solution to prepare a coating solution. Then, using a high coater (HCT-MINI, manufactured by FREUND), the tablets obtained in Preparation Examples 1 to 4 were supplied with an air supply temperature of about 70 ° C., a drum rotation speed of 30 rpm, a spray pressure of about 0.1 MPa, and a coating liquid injection. Under a condition of a speed of about 1.8 g / min, about 99 g of a coating liquid and about 15 g of a solid were coated on a tablet of about 300 g in total over about 1 hour. The weight increase of 14 tablets in each lot by the coating operation was as follows, and it was confirmed that the coating components covered the tablet surface.
Comparative preparation 1: 4.198 g → 4.543 g (Formulation 4)
Formulation 1: 4.265 g → 4.547 g (Formulation 5)
Formulation 2: 4.213 g → 4.529 g (Formulation 6)
Formulation 3: 4.225 g → 4.530 g (Formulation 7)
The formulation numbers of the coated tablets were designated as Formulations 4-7 as described above.

Reference Example 1
Preparation of the granules was performed as follows.
About 19.2 g of low-substituted hydroxypropylcellulose (L-HPC-32W) was added and dispersed in about 1128 mL of purified water, and then about 19.2 g of hydroxypropylcellulose (HPC-SL) was added and dispersed. About 120 g of Compound A was uniformly dispersed in the obtained polymer dispersion to obtain a coating liquid. About 1126 g of the coating liquid containing Compound A prepared above was coated on about 72 g of Selfia CP-305 as core particles using a coating apparatus (SPIR-A-FLOW). The coating conditions were as follows: INLET temperature about 60 ° C, spray pressure about 1 kgf / cm ² , exhaust air scale 100, BED pressure about 250 mmHg, rotor rotation speed about 300 rpm, spray injection speed about 2-8 g / Minutes, the spray position was at the bottom. After the completion of the coating operation, the mixture was sieved with a 1000 μm sieve, and the passed granules were further sieved with a 500 μm sieve, and the granules remaining on the sieve were collected and vacuum dried at 40 ° C. for about 24 hours. The weight of the granules (Reference Preparation 1) obtained after drying was about 170 g, and the content of Compound A was about 44.8% by weight of the granules.

Example 5
The granules obtained in Reference Example 1 were coated as follows.
About 3 g of triethyl citrate was dissolved in a mixture of about 388.8 g of ethanol and about 43.2 mL of purified water, and about 30 g of Eudragit S-100, which is a hydrophilic polymer, was dissolved. About 15 g of talc was uniformly dispersed in the obtained polymer solution to prepare a coating liquid. To about 70 g of the compound A-containing granules obtained in Reference Example 1 (Reference Preparation 1), about 331 g of the hydrophilic polymer-containing coating solution prepared above was applied using a coating apparatus (SPIR-A-FLOW). Coated. The coating conditions were: INLET temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 250 mmHg, rotor speed of about 150 rpm, spray injection speed of about 2-3 g. / Min, spray position at the bottom. After the completion of the coating operation, the mixture was sieved with a 1000 μm sieve, and the passed granules were further sieved with a 500 μm sieve, and the granules remaining on the sieve were collected and vacuum dried at 40 ° C. for about 24 hours. The weight of the granules (Formulation 8) obtained after drying was about 97 g, and the drug content was about 32.8% by weight of the granules.

Example 6
The granules obtained in Reference Example 1 were coated as follows.
About 3 g of triethyl citrate was dissolved in a mixture of about 388.8 g of ethanol and about 43.2 mL of purified water, and about 30 g of Eudragit L-100, which is a hydrophilic polymer, was dissolved. About 15 g of talc was uniformly dispersed in the obtained polymer solution to prepare a coating liquid. About 70 g of the compound A-containing granules obtained in Reference Example 1 (Reference Preparation 1) were coated with about 331 g of the hydrophilic polymer-containing coating solution prepared above using a coating apparatus (SPIR-A-FLOW). did. The coating conditions were about 40 ° C. The INLET temperature, the spray pressure of about 1kgf / cm ^2, exhaust air graduations 85-97, about 250 mmHg of BED pressure about 0.99 rpm rotor speed spray infusion rate of about 2 to 3 g / min, the spray position was at the bottom. After the completion of the coating operation, the mixture was sieved with a 1000 μm sieve, and the passed granules were further sieved with a 500 μm sieve, and the granules remaining on the sieve were collected and vacuum dried at 40 ° C. for about 24 hours. The weight of the granules (formulation 9) obtained after drying was about 101 g, and the drug content was about 33.5% by weight of the granules.

Example 7
For the granules obtained in Reference Example 1, Examples 5 and 6, the mixing ratio of Reference Preparation 1 / Preparation 8 / Preparation 9 was 1/6/3 (as the amount of Compound A) so that the Compound A content was 100 mg. And encapsulated in No. 1 capsule to give Formulation 10.

Example 8
The granules obtained in Examples 5 and 6 were mixed so that the compound A content was 50 mg, and the mixing ratio of Formulation 8 / Formulation 9 was 3/1 (as the amount of Compound A). To give Preparation 11.

Example 9
About 3 g of Compound A, about 600 mg of hydroxypropylmethylcellulose (Metroze 60SH-4000), about 3.3 g of polyethylene glycol (PEG6000), about 1.5 g of citric acid, about 600 mg of mannitol and about 90 mg of magnesium stearate, Approximately 303 mg was weighed and tableted at a tableting pressure of 2.5 ton / cm ^{2 into} a tablet having a diameter of 9 mm and a size of 7.5R to obtain Preparation 12.

Example 10
Coating of the tablet obtained in Example 9 was performed as follows.
About 2.5 g of polyethylene glycol 6000 and about 0.9 g of polysorbate 80 were dissolved in about 147 g of purified water as a plasticizer, and about 7.5 g of talc as a lubricant was uniformly dispersed. About 90 g of Eudragit L-30D-55 (trade name), which is a solution of the methacrylic acid copolymer, was added to this solution to prepare a coating solution. Next, for the preparation 12, using a high coater (HCT-MINI, manufactured by FREUND) under the conditions of an air supply temperature of about 70 ° C., a drum rotation speed of 30 rpm, a spray pressure of about 0.1 MPa, and a coating liquid injection rate of about 1.8 g / min. A total of about 300 g of tablets were coated with about 80 g as a coating liquid and about 12.2 g as a solid content over about 44 minutes. The weight increase of 10 tablets from the coating operation was about 3.047 g to about 3.289 g, and it was confirmed that the coating component covered the tablet surface.

Example 11
Coating of the tablet obtained in Example 9 was performed as follows.
About 3.6 g of triethyl citrate was dissolved as a plasticizer in about 81 g of purified water, and about 5.4 g of talc as a lubricant was uniformly dispersed. Approximately 30 g of Eudragit RL-30D (trade name) and RS-30D (trade name), which are solutions of the aminoalkyl methacrylate copolymer, were added to this solution to prepare a coating solution. Next, for the preparation 12, using a high coater (FREUND, HCT-MINI) under the conditions of an air supply temperature of about 50 ° C., a drum rotation speed of 30 rpm, a spray pressure of about 0.1 MPa, and a coating liquid injection rate of about 1.8 g / min. A total of about 300 g of tablets were coated with about 60 g as a coating liquid and about 10.8 g as a solid content over about 33 minutes. The weight increase of 10 tablets from the coating operation was about 3.042 g to about 3.228 g, and it was confirmed that the coating component was covering the tablet surface.

Reference Example 2
Preparation of the granules was performed as follows.
After dissolving about 7.2 g of mannitol in about 1176 mL of purified water, about 19.2 g of hydroxypropyl cellulose (HPC-SL) was added and dispersed, and about 19.2 g of low-substituted hydroxypropyl cellulose (L-HPC-32W) was added and dispersed. . About 120 g of Compound A was uniformly dispersed in the obtained polymer dispersion to obtain a coating liquid. About 1174 g of the coating liquid containing Compound A prepared above was coated on about 72 g of Selfia CP-507 as core particles using a tumbling fluidized bed coating apparatus (SPIR-A-FLOW). The coating conditions were: inlet temperature of about 60 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 250 mmHg, rotor speed of about 100 rpm, spray injection speed of about 2 to 8 g / min. And the spray position was on the lower side. After completion of the coating operation, the mixture was sieved with a 1180 μm sieve, and the passed granules were further sieved with a 710 μm sieve, and the granules remaining on the sieve were collected. The weight of the obtained granules (Reference preparation 2) was about 190 g, and the content of compound A was about 49% by weight of the granules.

Reference Example 3
Preparation of the granules was performed as follows.
After dissolving about 6.6 g of mannitol in about 607.2 mL of purified water, add and disperse about 17.6 g of hydroxypropylmethylcellulose (TC-5-EW), and add about 17.6 g of low-substituted hydroxypropylcellulose (L-HPC-32W). Dispersed. About 110 g of Compound A was uniformly dispersed in the obtained polymer dispersion to obtain a coating liquid. About 725 g of the coating solution containing Compound A prepared above was coated on about 72 g of Selfia CP-507 as core particles using a tumbling fluidized bed coating apparatus (SPIR-A-FLOW). The coating conditions are: inlet temperature of about 60 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 300 mmHg, rotor rotation speed of about 100 rpm, spray injection speed of about 8 g / min, The spray position was on the lower side. After completion of the coating operation, the mixture was sieved with a 1180 μm sieve, and the passed granules were further sieved with a 710 μm sieve, and the granules remaining on the sieve were collected. The weight of the obtained granules (Reference preparation 3) was about 200 g.

Reference example 4
Preparation of the granules was performed as follows.
After adding and dispersing about 6.6 g of crystalline cellulose (PH101) in about 619.5 mL of purified water, adding and dispersing about 17.6 g of hydroxypropylmethyl cellulose (TC-5-EW), low-substituted hydroxypropyl cellulose (L-HPC-32W) Was added and dispersed, and about 3.1 g of light anhydrous silicic acid (Aerosil) was further added and dispersed. About 110 g of Compound A was uniformly dispersed in the obtained polymer dispersion to obtain a coating liquid. About 739 g of the coating solution containing Compound A prepared above was coated on about 72 g of Selfia CP-507 as core particles using a tumbling fluidized bed coating apparatus (SPIR-A-FLOW). The coating conditions are: inlet temperature of about 60 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 300 mmHg, rotor rotation speed of about 100 rpm, spray injection speed of about 8 g / min, The spray position was on the lower side. After completion of the coating operation, the mixture was sieved with a 1180 μm sieve, and the passed granules were further sieved with a 710 μm sieve, and the granules remaining on the sieve were collected. The weight of the obtained granules (Reference preparation 4) was about 200 g.

Example 12
The granules obtained in Reference Example 2 were coated as follows.
About 5.9 g of triethyl citrate was dissolved in a mixture of about 763.4 g of ethanol and about 84.8 mL of purified water, and about 44.2 g of Eudragit S-100 and about 14.7 g of Eudragit L-100 were dissolved. About 29.5 g of talc was uniformly dispersed in the obtained polymer solution to prepare a coating liquid. About 170 g of the compound A-containing granules obtained in Reference Example 2 (Reference Preparation 2), the polymer-containing coating liquid prepared above was applied to a rolling fluidized bed coating apparatus (SPIR-A-FLOW) for about 900 g. g coated. The coating conditions were: inlet temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 290 mmHg, rotor speed of about 100 rpm, spray injection speed of about 4-5 g. / Min, spray position on the lower side. After the completion of the coating operation, the mixture was sieved with a 1400 μm sieve, and the passed granules were further sieved with a 850 μm sieve, and the granules remaining on the sieve were collected. The weight of the obtained granules (Formulation 15) was about 237 g, and the drug content was about 32% by weight of the granules.

Example 13
With respect to the granules obtained in Example 12, Formulation 15 was encapsulated in No. 3 capsules so that Compound A content became 50 mg, to obtain Formulation 16.

Example 14
The granules obtained in Reference Example 3 were coated as follows.
After dissolving about 2.2 g of triethyl citrate in a mixture of about 285.8 g of ethanol and about 31.8 mL of purified water, about 16.5 g of Eudragit S-100 and about 5.5 g of Eudragit L-100 were dissolved. About 11.0 g of talc was uniformly dispersed in the obtained polymer solution to prepare a coating liquid. About 70 g of the compound A-containing granules obtained in Reference Example 3 (Reference Preparation 3), about 370 g of the polymer-containing coating liquid prepared above was applied using a tumbling fluidized bed coating apparatus (SPIR-A-FLOW). g coated. The coating conditions are: inlet temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 300 mmHg, rotor rotation speed of about 100 rpm, spray injection speed of about 4 to 5 g. / Min, spray position on the lower side. After the completion of the coating operation, the mixture was sieved with a 1400 μm sieve, and the passed granules were further sieved with a 850 μm sieve, and the granules remaining on the sieve were collected. The weight of the obtained granules (Formulation 17) was about 85 g, and the drug content was about 33% by weight of the granules.

Example 15
The granules obtained in Reference Example 4 were coated as follows.
After dissolving about 2.2 g of triethyl citrate in a mixture of about 285.8 g of ethanol and about 31.8 mL of purified water, about 16.5 g of Eudragit S-100 and about 5.5 g of Eudragit L-100 were dissolved. About 11.0 g of talc was uniformly dispersed in the obtained polymer solution to prepare a coating liquid. About 70 g of the compound A-containing granules obtained in Reference Example 3 (Reference Preparation 4), about 370 g of the polymer-containing coating solution prepared above was applied using a tumbling fluidized bed coating apparatus (SPIR-A-FLOW). g coated. The coating conditions are: inlet temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale of 100, BED pressure of about 300 mmHg, rotor rotation speed of about 100 rpm, spray injection speed of about 4 to 5 g. / Min, spray position on the lower side. After the completion of the coating operation, the mixture was sieved with a 1400 μm sieve, and the passed granules were further sieved with a 850 μm sieve, and the granules remaining on the sieve were collected. The weight of the obtained granules (Formulation 18) was about 85 g, and the drug content was about 32% by weight of the granules.

Experimental example 1
The coated tablet (Formulation 4) obtained in Example 4 was orally administered to a beagle dog (male, body weight: about 10 kg), and the subsequent change in the concentration of Compound A in plasma was examined. For comparison, the tablet (Comparative Preparation 1) obtained in Comparative Example 1 was orally administered to a beagle dog in the same manner, and the subsequent change in the plasma concentration of Compound A was examined. The result is shown in FIG.
As shown in FIG. 1, the sustained-release blood concentration of the physiologically active ingredient (Compound A) was obtained by the controlled release composition of the present invention.

Experimental example 2
The coated tablets (Formulations 5 to 7) obtained in Example 4 were orally administered to beagle dogs (male, body weight: about 10 kg), and the subsequent changes in the plasma concentration of Compound A were examined. The result is shown in FIG.
As shown in FIG. 2, the sustained-release blood concentration of the physiologically active ingredient (Compound A) was obtained by the controlled release composition of the present invention.

Experimental example 3
The capsule (Formulation 10) obtained in Example 7 was orally administered to a beagle dog (male, body weight: about 10 kg), and the subsequent change in the concentration of Compound A in plasma was examined. The result is shown in FIG.
As shown in FIG. 3, the sustained-release blood concentration of the physiologically active ingredient (Compound A) was obtained by the controlled release composition of the present invention.

Experimental example 4
The capsule (formulation 11) obtained in Example 8 was orally administered to a cynomolgus monkey (male, body weight: about 4 kg), and the subsequent change in the plasma concentration of compound A was examined. The result is shown in FIG.
As shown in FIG. 4, sustained blood concentration of the physiologically active ingredient (Compound A) was obtained by the controlled release composition of the present invention.

Experimental example 5
The coated tablets (Formulations 13 and 14) obtained in Examples 10 and 11 were orally administered to beagle dogs (male, body weight: about 10 kg), and the subsequent changes in the plasma concentration of Compound A were examined. The result is shown in FIG.
As shown in FIG. 5, the sustained-release blood concentration of the physiologically active ingredient (Compound A) was obtained by the controlled release composition of the present invention.

Experimental example 6
The capsule (Formulation 16) obtained in Example 13 was orally administered to a cynomolgus monkey (male, body weight: about 4 kg), and the subsequent change in the plasma concentration of Compound A was examined. FIG. 6 shows the result.
As shown in FIG. 6, sustained blood concentration of the physiologically active ingredient (Compound A) was obtained by the controlled release composition of the present invention.

According to the present invention, there is provided a controlled release composition for oral administration of an imidazole derivative having a steroid C _17,20 lyase inhibitory activity, which has a markedly improved blood concentration persistence.

FIG. 2 is a graph showing the time-dependent changes in the plasma concentration of a physiologically active substance after oral administration to dogs of the membrane-coated release controlled composition of the present invention and an immediate release tablet having no coating layer. FIG. 3 is a graph showing the time-dependent changes in the plasma concentration of a physiologically active substance after oral administration to dogs of three membrane-coated release controlling compositions of the present invention having nuclei containing different hydrophilic polymers. BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows the time-dependent change of the plasma concentration of the physiologically active substance after the dog oral administration of the mixed release control composition of this invention. It is a figure which shows the time-dependent change of the plasma concentration of the physiologically active substance after the monkey oral administration of the mixed release control composition of this invention. BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which shows the time-dependent change of the plasma concentration of the physiologically active substance after the dog oral administration of the mixed release control composition of this invention. It is a figure which shows the time-dependent change of the plasma concentration of the physiologically active substance after the monkey oral administration of the controlled release composition of this invention.

Claims (23)

formula:

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a physiologically active substance which is a salt thereof, and a hydrophilic polymer. And a controlled release composition for oral administration. formula:

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent). A controlled release composition for oral administration which is coated with a coating layer containing The controlled release composition according to claim 1 or 2, wherein the solubility (37 ° C) of the physiologically active substance in the first liquid of the Japanese Pharmacopoeia Disintegration Test is about 0.1 mg / mL or more. 2. The controlled release composition according to claim 1, having the following dissolution characteristics:
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid, the release control composition 15 minutes after the start of the test in the Japanese Pharmacopoeia dissolution test method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C) The dissolution rate of the physiologically active substance from the substance is less than 40%, and 2) Japanese Pharmacopoeia dissolution test method 2 using 900 mL of the second liquid of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed) (50 rpm, 37 ° C.), the dissolution rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 40% or more. (1 set:

(Wherein, n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent.) Or a physiologically active substance which is a salt thereof,
(2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, carboxymethylcellulose sodium and a hydrophilic polymer selected from low-substituted hydroxypropylcellulose and
(3) A controlled-release composition for oral administration containing a lubricant selected from magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate and magnesium metasilicate aluminate. 3. The controlled release composition according to claim 2, having the following dissolution characteristics:
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid, the release control composition 15 minutes after the start of the test in the Japanese Pharmacopoeia dissolution test method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C) The dissolution rate of the physiologically active substance from the substance is less than 10%, and 2) the Japanese Pharmacopoeia dissolution test method 2nd method using 900 mL of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed) (50 rpm, 37 ° C.), the dissolution rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 40% or more. Equation (A) (1):

(Wherein, n is an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent) or a physiologically active substance which is a salt thereof.
(2) a core containing a hydrophilic polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose,
(B) (1) cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer,
(2) a lubricant selected from magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate and magnesium aluminate metasilicate and
(3) selected from acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin and triethyl citrate A controlled release composition for oral administration which is coated with a coating layer containing a plasticizer. The controlled release composition according to claim 2, wherein the release of the physiologically active substance in the absence of the coating layer is immediate release. 3. The controlled release composition according to claim 2, wherein the core is a controlled release matrix further comprising a hydrophilic polymer. The controlled release composition according to claim 1 or 9, wherein the content of the hydrophilic polymer is about 3% to about 95% by weight. The controlled release composition according to claim 2, wherein the polymer in the coating layer exhibits pH-dependent or delayed-solution type water solubility. The controlled release composition according to claim 2, wherein the polymer in the coating layer is water-insoluble or poorly water-soluble. The controlled release composition according to claim 1 or 2, which contains the same or different physiologically active substance as the physiologically active substance contained in the controlled release composition, and the release of the physiologically active substance is rapid release. A controlled release composition coated with a coating layer. 3. The controlled release composition according to claim 1, which is used for prevention or treatment of prostate cancer or breast cancer. A composition comprising a combination of the controlled release composition according to claim 1 or 2 and one or more other controlled release compositions different in release rate of a physiologically active substance from the controlled release composition. The composition according to claim 15, wherein the other controlled release composition contains a physiologically active substance having a solubility (37 ° C) in the first liquid of the Japanese Pharmacopoeia disintegration test of about 0.1 mg / mL or more. The bioactive agent in another controlled release composition has the formula:

(Wherein n is an integer of 1 to 3, and Ar represents an aromatic ring which may have a substituent) or a salt thereof. 18. The composition according to claim 17, having the following dissolution characteristics:
1) In the Japanese Pharmacopoeia disintegration test, 900 mL of the first liquid, the release control composition 15 minutes after the start of the test in the Japanese Pharmacopoeia dissolution test method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C) The dissolution rate of the physiologically active substance from the substance is less than 10%, and 2) the Japanese Pharmacopoeia dissolution test method 2nd method using 900 mL of the Japanese Pharmacopoeia disintegration test (paddle method, paddle rotation speed) (50 rpm, 37 ° C.), the dissolution rate of the physiologically active substance from the controlled release composition 24 hours after the start of the test is 20% or more. The composition according to claim 15, wherein the release of the physiologically active substance in the other controlled release composition is immediate release. Another controlled release composition, characterized in that a nucleus containing a physiologically active substance is coated with a coating layer containing a polymer exhibiting pH-dependent or dissolution-deteriorated water-soluble property, 16. The composition according to 15. The composition according to claim 15, which is used for prevention or treatment of prostate cancer or breast cancer. (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or a salt thereof,
(2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, hydrophilic polymer selected from sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose,
(3) lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, disintegrant selected from light anhydrous silicic acid and low-substituted hydroxypropylcellulose,
(4) Magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, a lubricant selected from synthetic aluminum silicate and magnesium metasilicate aluminate,
(5) cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer,
(6) From pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone Binder and chosen
(7) selected from acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin and triethyl citrate A controlled-release composition for oral administration comprising a plasticizer. (A) (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or a salt thereof and
(2) a core containing a hydrophilic polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose,
(B) (1) cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, enteric coating agent selected from hydroxymethylcellulose acetate succinate and methacrylic acid copolymer,
(2) a lubricant selected from magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate and magnesium aluminate metasilicate and
(3) selected from acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono- and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin and triethyl citrate A controlled release composition for oral administration which is coated with a coating layer containing a plasticizer.

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