JP4837895B2 - Controlled release composition - Google Patents

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

  Orally administered preparations such as tablets, capsules and granules are easy to take and safer than injections, and are the dosage forms used most frequently in the medical field. In recent years, for the purpose of improving QOL (Quality Of Life) of patients and providing labor-saving and economical medical care, oral administration preparations having long-lasting medicinal effects by administration once or twice a day have been developed.

  Drugs that are highly water-soluble under acidic conditions are quickly dissolved and absorbed in the stomach in normal immediate-release preparations, so the duration of effective blood concentration is short and the initial blood concentration after administration There are problems such as the development of toxicity due to the sudden rise in drug concentration. Therefore, development of a controlled-release preparation imparted with sustained release or non-release particularly in the stomach is strongly desired. However, some drugs do not exhibit blood pharmacokinetics as expected from in vitro dissolution tests in vivo, and there are many drugs for which effective controlled release formulations for oral administration have not yet been obtained. is the current situation.

International Publication No. 02/40484 Pamphlet

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

As a result of intensive studies to achieve the above object, the present inventors include a physiologically active substance (for example, a steroid C _17,20 lyase inhibitor) in a matrix base composed of a hydrophilic polymer. Alternatively, by coating the core containing the physiologically active substance with a coating layer containing a polymer, the maximum blood concentration is remarkably reduced as compared with the immediate release preparation, and then sustained for a long time thereafter. We have found that drug release can be realized. Furthermore, the sustainability of effective blood concentration is improved by using granules containing steroid C _17,20 lyase inhibitor nuclei coated with a coating layer containing a polymer with pH-dependent water solubility. Succeeded in doing. As a result of further studies based on these findings, the present inventors 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 represents an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent) and a physiologically active substance which is a salt thereof and a hydrophilic polymer Containing a controlled release composition for oral administration;
[2] Formula:

(Wherein n represents an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent), a nucleus containing a physiologically active substance which is a compound represented by A controlled release composition for oral administration, coated with a coating layer containing
[3] The controlled release composition according to [1] or [2] above, 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 as described in [1] above, which has the following elution characteristics:
1) 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) using 900 mL of the first solution of the Japanese Pharmacopoeia Disintegration Test The elution rate of biologically active substances from the product is less than 40%, and 2) Japanese Pharmacopoeia Dissolution Test Method 2 using the second solution 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 controlled release composition 24 hours after the start of the test is 40% or more;
[5] Formula (1):

(Wherein n represents 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, Hydrophilic polymers selected from hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose and (3) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, 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 as described in [2] above, which has the following elution characteristics:
1) 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) using 900 mL of the first solution of the Japanese Pharmacopoeia Disintegration Test The elution rate of the physiologically active substance from the product is less than 10%, 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 elution 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 represents an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent) and a physiologically active substance which is a compound or a salt thereof and (2) hydroxypropylcellulose, A nucleus containing a hydrophilic polymer selected from hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose;
(B) (1) Enteric coating agent selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (2) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloid Lubricant selected from silica, synthetic aluminum silicate and magnesium aluminate metasilicate 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 according to the above [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 the above [2], wherein the nucleus is a controlled release matrix further comprising a hydrophilic polymer;
[10] The controlled release composition according to the above [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 [2], wherein the polymer in the coating layer exhibits pH-dependent or dissolution-retarded 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 release controlling composition according to the above [1] or [2] contains a physiologically active substance that is the same or different from the physiologically active substance contained in the controlled release composition, and the release property of the physiologically active substance A controlled release composition comprising a coating layer having a rapid release property;
[14] The controlled release composition according to [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 the physiologically active substance. object;
[16] The composition according to [15] above, wherein the other controlled release composition contains a physiologically active substance having a solubility (37 ° C.) in the first solution of the Japanese Pharmacopoeia disintegration test of about 0.1 mg / mL or more;
[17] The physiologically active substance in the other controlled release composition has the formula:

(Wherein n represents an integer of 1 to 3 and Ar represents an aromatic ring which may have a substituent) or a salt thereof, the composition according to [16] above;
[18] The composition according to [17] above, which has the following elution characteristics:
1) 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) using 900 mL of the first solution of the Japanese Pharmacopoeia Disintegration Test The elution rate of the physiologically active substance from the product is less than 10%, 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 elution 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 according to [15] above, wherein the release of the physiologically active substance in the other controlled release composition is immediate release;
[20] Another release controlling composition is characterized in that a core containing a physiologically active substance is coated with a coating layer containing a pH-dependent or dissolution-retarding water-soluble polymer. The composition according to [15] above;
[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) Hydrophilic polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, (3) lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium Disintegrant selected from sodium croscarmellose, 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 acid (5) Enteric coating agent selected from cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, 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) Acetyl tributyl citrate, acetyl triethyl 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 (B) (1) cellulose containing a hydrophilic polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose. Enteric coating agents selected from 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 Metasilicate aluminum A lubricant selected from magnesium 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, Disclosed 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 provides a physiologically active substance having the formula:

(Wherein n represents an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent), or a salt thereof, and a hydrophilic polymer. Provided are controlled release compositions for oral administration.
In the present specification, the “release controlled composition for oral administration” means that the release profile after oral administration of a physiologically active substance contained in the composition is controlled to be different from that in the administration of the physiologically active substance itself. And includes any controlled release rate that is lower (sustained release), more controlled (acceleration of dissolution), or controlled release time (dissolution delay). Further, a combination of these two or more controls is also included. Further, it is not necessary to control the release throughout the elution process, and as long as the release is controlled in a part of the dissolution process, 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。 Preferable examples of the compound represented by the formula (I) -A include the following compounds:
[1] In the formula, Ar is a monocyclic or bicyclic aromatic condensed ring which may have a substituent,
[2] A compound in which Ar may be substituted and is an aromatic ring composed of 5 to 10 atoms containing 0 to 4 heteroatoms as ring members 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, and Ra ¹ and Ra ² are the same or different and each represents a hydrogen atom, a hydroxyl group optionally having a substituent, or a substituent. A thiol optionally having a substituent, an amino optionally having a substituent, an acyl, a halogen atom or a hydrocarbon group optionally having a substituent, a group represented by the formula:

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

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

(Wherein Ra ⁶ and Ra ⁷ are the same or different and each represents 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, a hydrogen atom, a hydroxyl group optionally having a substituent, a thiol optionally having a substituent, An amino, acyl, halogen atom which may have a substituent or a hydrocarbon group 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 represents a hydrogen atom or lower alkyl),
[6] A compound in which the configuration is an enantiomer having an S configuration, and [7] a compound in which the configuration is an enantiomer having an R configuration.

The definition of each symbol in each formula is as follows.
n is an integer of 1 to 3, with 1 being preferred.
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, 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, 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, particularly preferably 0.

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

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 preferable. Examples of the “alkyl” include C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc. C _1-6 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 _2-10 alkenyl such as sec- butenyl C _{2 -6} alkenyl (eg, vinyl, 1-propenyl, allyl, etc.) is preferred. Examples of the “alkynyl” include C _2-10 alkynyl such as ethynyl, 1-propynyl, propargyl and the like, and C _2-6 alkynyl (eg, ethynyl etc.) 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.
Examples of the “alicyclic hydrocarbon group” include monocyclic or condensed polycyclic groups composed of, for example, 3 to 10 carbon atoms, specifically cycloalkyl, cycloalkenyl, and C _{6- 14-} aryl (for example, benzene etc.) etc. 2 or 3 ring fused ring etc. are mentioned. Examples of the “cycloalkyl” include C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and examples of the “cycloalkenyl” include C 3 such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. _{And 3-6} cycloalkenyl.
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. C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and the like, and C _6-10 aryl (for example, phenyl) and the like are preferable.

  The substituent that the “chain hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” may have is not particularly limited, but for example, a halogen atom, a hydroxyl group, alkoxy, acyloxy Alkylthio, acylamino, carboxyl, alkoxycarbonyl, oxo, alkylcarbonyl, cycloalkyl, aryl, aromatic heterocyclic group and the like. These substituents are substituted on the “chain hydrocarbon group” within a chemically acceptable range, and the number of substituents of the substituent is 1 to 5, preferably 1 to 3. However, when the number of substituents is 2 or more, they may be the same or different.

  The substituent that the “cyclic hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” may have is not particularly limited, but for example, a halogen atom, a hydroxyl group, alkoxy, acyloxy Alkylthio, alkylsulfonyl, mono- or di-alkylamino, acylamino, carboxyl, alkoxycarbonyl, alkynylcarbonyl, alkyl, cycloalkyl, aryl, aromatic heterocyclic group and the like. These substituents are substituted on the “cyclic hydrocarbon group” within a chemically acceptable range, and the number of substituents of the substituent is 1 to 5, preferably 1 to 3. However, when the number of substituents is 2 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, hexyloxy and the like. Examples of the “acyloxy” include formyloxy, C _1-10 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.) and the like. Examples of the “alkylthio” include C _1-10 alkylthio such as methylthio, ethylthio, propylthio, isopropylthio and the like. Examples of the “alkylsulfonyl” include C _1-10 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like. Examples of the “acylamino” include formylamino, diformylamino, mono- or di-C _1-10 alkyl-carbonylamino (eg, acetylamino, propionylamino, butyrylamino, diacetylamino, etc.) and the like. Examples of the “mono- or di-alkylamino” include those similar to the above-mentioned lower alkylamino and di-lower alkylamino. Examples of the “alkoxycarbonyl” include C _1-10 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like. 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, 2-propynylcarbonyl and the like. Examples of the “cycloalkyl” include C _3-10 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of the “aryl” include C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl and the like. The “aromatic heterocyclic group” is, for example, a 1 to 3 cyclic aromatic heterocyclic group containing one or two, preferably 1 to 4, heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms. Etc. 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, pentyl and the like.

The substituent that the “hydrocarbon group” may have further has 1 to 5, preferably 1 to 3 substituents within the chemically acceptable range as shown below. 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 is, for example, 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.

Examples of the aromatic ring optionally having a substituent represented by Ar include a monocyclic or bicyclic aromatic condensed ring which may have one or more substituents. Further, it may be substituted, and is an aromatic ring composed of 5 to 10 atoms containing 0 to 4 heteroatoms as ring-constituting atoms (wherein the aromatic ring is not a heteroatom but a carbon atom and has the formula ( I) (which is bonded to the fused imidazole ring in -A) is also preferably exemplified as Ar.
Examples of the substituent in the aromatic ring optionally having a substituent represented by Ar include a hydroxyl group that may have a substituent, a thiol that may have a substituent, and a substituent. Examples thereof include an amino group, an acyl group, a halogen atom or a hydrocarbon group which may have a substituent. The “optionally substituted hydroxyl group”, the “optionally substituted amino”, the “acyl”, the “halogen atom”, and the “optionally substituted” 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, such as an acid addition salt such as an inorganic acid salt (for example, hydrochloride, sulfate, hydrobromide, phosphorus Acid salts), organic acid salts (eg acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methane Sulfonates, p-toluenesulfonates, etc.).
The compound represented by the general formula (I) -A or a salt thereof may be a hydrate, both of which are within the scope of the present invention. Hereinafter, it is referred to as Compound (I) -A including salts and hydrates.

The compound represented by the formula (I) -A and a prodrug thereof have an excellent effect as a medicine, and particularly have an excellent inhibitory activity against steroid C _17,20 lyase. Since these compounds have low toxicity and few side effects, they can be used against mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, etc., especially humans), for example (i) androgens or An estrogen-lowering drug [ie, a drug having an action of suppressing the production of androgen and the subsequent production of estrogen (estrogen is synthesized using androgen as a substrate)], (ii) a disease related to androgen or estrogen, for example, (1) Primary cancer, metastasis or recurrence of malignant tumors (eg, prostate cancer, breast cancer, uterine cancer, ovarian cancer, etc.), (2) symptoms associated with those cancers (eg, pain, cachexia, etc.), ( 3) Various types such as benign prostatic hyperplasia, masculinosis, hirsutism, male pattern baldness, male prematurity, endometriosis, uterine fibroids, uterine adenomyosis, mastopathy, polycystic ovary syndrome It is useful as a therapeutic and prophylactic agent for diseases, preferably prostate cancer, breast cancer and the like.

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.
As a prodrug of compound (I) -A, a compound 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.); 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, pivaloylated, 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. As such salts, when the prodrug of the compound (I) -A has an acidic group such as carboxyl, an inorganic base (eg, alkali metal such as sodium or potassium, alkaline earth metal such as calcium or magnesium, zinc , Transition metals such as iron and copper) 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 and ornithine) and the like.

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

  Among the compounds of 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] L] -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 and the like are preferable. In particular, (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide is preferred.

  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 exhibits high water solubility under acidic conditions. Specifically, the first liquid of the Japanese Pharmacopoeia disintegration test at 37 ° C. Solubility in water (hereinafter sometimes abbreviated as “solubility (Part 1), 37 ° C.)” is 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 the physiologically active substance dispersed in the gel, or itself in water. It means a polymer that can control the release of a physiologically active substance by dissolving it, or 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 wt% aqueous solution (measurement 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 or the blending 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, Nippon Soda Co., Ltd.) (viscosity of 2 wt% 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 wt% 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) (Manufactured by Co., Ltd.) (Hydroxypropyl cellulose such as 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% aqueous solution at 20 ° C: approx. 3 mPa · s), TC-5EW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C) SB-4 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: about 4 mPa · s), TC-5MW ( Product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2 wt% aqueous solution at 20 ° C: about 4.5 mPa · s) TC-5R (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 wt% at 20 ° C) Viscosity of aqueous solution: approx. 6 mPa · s), TC-5RW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C: approx. 6 mPa · s), TC-5S (trade name, Shin-Etsu) (Made by Chemical Industry Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 15 mPa · s), Metrose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C) : Approx. 50 mPa · s), Metro 65SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: approx. 50 mPa · s), Metrows 90SH-100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) ( Viscosity of 2 wt% aqueous solution at 20 ° C: approx. 100 mPa · s), Metrows 65SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 400 mPa · s), Metrows 90SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: about 400 mPa · s), Metrose 65SH-1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 Viscosity of 2 wt% aqueous solution at ℃: approx. 1500 mPa · s), Metrows 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 4000 mPa · s), Metrows 65SH -4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C: approx. 4000 mPa · s), Metroise 90SH-4 000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C: about 4000 mPa · s), Metroles 90SH-30000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (at 20 ° C Hydroxypropyl methylcellulose such as 2% aqueous solution viscosity: about 30000 mPa · s);
Metrows SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity: approx. 15 mPa · s, 2 wt% aqueous solution, 20 ° C), Metrows SM25 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 at 20 ° C) Viscosity of weight% aqueous solution: approx. 25 mPa · s), Metrows SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C .: approx. 100 mPa · s) (Chemical Industry Co., Ltd.) (Viscosity of 2 wt% aqueous solution at 20 ° C: approx. 400 mPa · s), Metrows SM1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2 wt% aqueous solution at 20 ° C: approx. 1500mPa · s), Metrows SM4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: approximately 4000mPa · s), Metrows SM8000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% by weight aqueous solution at 20 ° C .: about 8000 mPa · s)
WSR N-12K (trade name, manufactured by Union Carbide) (viscosity of 2 wt% aqueous solution at 20 ° C: 400 to 800 mPa · s), WSR N-60K (trade name, manufactured by Union Carbide) (2 weight at 20 ° C) % Aqueous solution viscosity: 2000-4000 mPa · s), WSR 301 (trade name, manufactured by Union Carbide) (1% aqueous solution viscosity at 25 ° C: 1500-4500 mPa · s), WSR Coagulant (trade name, Union Carbide) (Viscosity of 1 wt% aqueous solution at 25 ° C: 4500-7500 mPa · s), WSR 303 (trade name, manufactured by Union Carbide) (Viscosity of 1 wt% aqueous solution at 25 ° C: 70000 to 10,000 mPa · s), WSR Polyethylene oxide such as 308 (trade name, manufactured by Union Carbide) (viscosity of 1 wt% aqueous solution at 25 ° C .: 10000 to 15000 mPa · s);
Sunrose F-150MC (trade name, manufactured by Nippon Paper Industries Co., Ltd.) (viscosity of 1 wt% aqueous solution at 25 ° C: 1200-1800 mPa · s), Sunrose F-300MC (trade name, manufactured by Nippon Paper Industries Co., Ltd.) (at 25 ° C Viscosity of 1 wt% aqueous solution: 2500-3000 mPa · s), Sunrose F-1000MC (trade name, manufactured by Nippon Paper Industries Co., Ltd.) (viscosity of 1 wt% aqueous solution at 25 ° C: 8000-12000 mPa · s) ;
LH-11 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-21 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-31 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH- 22 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-32 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-20 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-30 ( Low-substituted hydroxypropylcellulose such as a trade name, manufactured by Shin-Etsu Chemical Co., Ltd.). Two or more kinds of these hydrophilic polymers may be mixed 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 physiologically active substance, the size of the preparation, etc., but is, for example, 1 to 90% by weight, preferably 5 to 85% by weight, more preferably 10%. ~ 80 wt%.
Further, 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 kind of the hydrophilic polymer, etc., for example, 3 to 95% by weight, preferably 5 to 95% by weight, more preferably 5 to 90% by weight.

The controlled release composition has an acidic pH (for example, pH 1 to 3) corresponding to elution near the stomach in the early stage after oral administration by having the above-mentioned physiologically active substance and hydrophilic polymer in the above-described contents. Elution of the physiologically active substance in water is suppressed, and the elution of the physiologically active substance takes a long time after the small intestine, especially in the weakly acidic to weakly alkaline (e.g., pH 5 to 8) equivalent to the elution in the small intestine Persisted.
Specifically, in the above controlled release composition,
1) 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) using 900 mL of the first solution of the Japanese Pharmacopoeia Disintegration Test The elution rate of physiologically active substances from is less than 40%,
2) In the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C) using 900 mL of the second solution of the Japanese Pharmacopoeia Disintegration Test, a controlled release composition 24 hours after the start of the test The elution rate of the physiologically active substance from is 40% or more.

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

  Said release control composition can be manufactured by mixing and molding the above-mentioned physiologically active substance and hydrophilic polymer in the above-mentioned contents. Here, mixing and molding can be performed according to a method commonly used in the pharmaceutical technical field. 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。 Further, a pharmacologically acceptable carrier may be used during mixing and / or molding. Examples of the “pharmacologically acceptable carrier” include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants. Further, if necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used.
Suitable 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 And light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate, magnesium metasilicate aluminate and the like.
Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Suitable examples of colorants include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, and edible blue Nos. 1 and 2), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, β-carotene, chlorophyll, bengara) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
Specifically, preferred among the above-mentioned controlled release compositions is the formula (1):

(Wherein n represents 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, Hydrophilic polymers selected from hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose and (3) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic silicic acid It comprises a lubricant selected from aluminum and magnesium aluminate metasilicate.

The physiologically active substances contained in the above-mentioned controlled release composition are weakly acidic to weakly alkaline and have relatively low water solubility, so that elution and absorption of the physiologically active substances after the small intestine is not possible when used as a preparation for oral administration. When there is a possibility that it will be sufficient, a pH adjusting agent or other solubilizing aid 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 the change in drug dissolution due to the environmental pH. In addition, since the in-vivo pH may vary among individual patients, in order to obtain a uniform medicinal effect for various patients, it is extremely significant to reduce changes in drug elution due to environmental pH.
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, glutamic acid, and salts thereof (for example, nitric acid citrate). Sodium hydrogen, disodium citrate, calcium citrate, monosodium fumarate, monosodium succinate, sodium aspartate, magnesium aspartate, arginine glutamate, potassium glutamate, sodium glutamate, etc.), inorganics such as phosphoric acid, hydrochloric acid, sulfuric acid Examples include acids and salts thereof (for example, potassium dihydrogen phosphate, sodium dihydrogen phosphate, etc.), acidic polymers such as carboxyvinyl polymer, and salts thereof. Of these, citric acid, tartaric acid, fumaric acid, ascorbic acid, aspartic acid, glutamic acid and salts thereof are preferable. Examples of other solubilizers include cyclodextrins such as β-cyclodextrin and maltosyl-β-cyclodextrin, surfactants such as polysorbate 80 and glyceryl monostearate, polyethylene glycol 4000 and polyethylene glycol. Examples include polyethylene glycol such as 6000.
The content of the pH adjusting agent or other solubilizing agent varies depending on the type and content of the physiologically active substance, the size of the composition, etc., but is, for example, 1 to 50% by weight, preferably 5 to 40% by weight.

  When the controlled release composition is a granule, for example, while spraying a binder dissolved in a suitable solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles, the above physiological activity Rolling granulation method, pan coating method, fluidized bed in which substances and hydrophilic polymers, or a mixture of these and excipients, lubricants, etc. are added 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 Malmo method, or the like. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size 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 bioactive substance and mixed (if necessary, further kneaded. And can be prepared by compression molding.

Since the above-mentioned controlled release composition has low toxicity and few side effects, it can be safely administered orally to mammals (eg, humans, cows, horses, pigs, dogs, cats, monkeys, mice, rats, etc., particularly humans). In particular, it can be used as a therapeutic and prophylactic agent for the above-mentioned various diseases, preferably prostate cancer and breast cancer, which can obtain 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 physiologically active substance, the subject to be administered, the number of times of administration, etc., but for example, when administered orally to an adult solid tumor patient (for example, prostate cancer patient). 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 above-mentioned controlled release composition can be further enhanced by using it in combination with other physiologically active substances having medicinal effects. Examples of other physiologically active substances having medicinal properties include “sex hormone agents (hormonal agents)”, “alkylating agents”, “antimetabolites”, “anticancer antibiotics”, “plant alkaloids”, “immunity” Therapeutic agents ”,“ drugs that inhibit 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 phosfestol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin , Raloxifene, olmeroxifene, levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate), pill preparations, 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, ethinylestradiol sulfonate, aromatase inhibitor (eg, fadrozol hydrochloride, anastrozole, letrozole, exemestane, borozole, 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 (eg For example, riarosol and the like).

  Examples of the `` alkylating agent '' include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Prednimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide, dino Tati Nsu Chima Lamar, adozelesin, system scan Chin, Bizereshin, and the like.

  “Antimetabolites” include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexim, idoxyuridine, thiazoline, etc. Can be mentioned.

  Examples of the “anticancer antibiotic” include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin 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 `` immunotherapy agent (BRM) '' include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacteria Umparbum, levamisole, polysaccharide K, procodazole and the like can be mentioned.

  The “cell growth factor” in the “drug that inhibits the action of 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 particular, there may be mentioned factors that exert an action at a low concentration by binding to a receptor. Specifically, (1) EGF (epidermal growth factor) or a substance having substantially the same activity (eg, EGF) , Heregulin (HER2 ligand), etc.], (2) insulin or a substance having substantially the same activity [eg, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), (3) FGF (fibroblast growth factor) or a substance having substantially the same activity (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 that has the ability to bind to the above-mentioned cell growth factor. Specifically, EGF receptor, HER2 (heregulin receptor), Examples include insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2.

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

  In addition to the above-mentioned 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) [for example, an LHRH receptor agonist (for example, goserelin acetate, buserelin acetate, leuprorelin acetate, etc.) or an LHRH receptor antagonist (for example, ganirelix, cetrorelix, abarelix, etc. In combination with these, androgen or estrogen in the blood can be more effectively removed.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. 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, symptom, 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 with respect to 1 part by weight of the physiologically active substance described above.

  The present invention also covers a core containing the compound represented by the 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 controlled release membrane. Or a controlled release composition for oral administration (hereinafter sometimes abbreviated as “film-coated release control composition”). However, the coating layer does not contain a physiologically active substance (including a substance different from the physiologically active substance contained in the nucleus). Here, the “physiologically active substance” means a substance contained so as to achieve a desired medicinal effect, and does not include a substance blended as a pharmaceutical additive such as an excipient.

  The polymer contained in the coating layer (hereinafter also referred to as “coating polymer” in the present specification) is a pharmacologically acceptable polymer that releases the 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 are also no particular restrictions on the type of release control membrane, for example, 1) having a relatively large micropore, such as a porous membrane, and controlling the release of inclusions through the micropore, 2) non-porous film Examples of membranes include those that control the release of inclusions by diffusion through molecular chain gaps accompanying 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 1) and 2), as the coating polymer, for example, a water-insoluble or poorly water-soluble polymer, etc., and in the case of 3), for example, a pH-dependent or dissolution-retarded water solubility is exhibited. Polymers and the like can be used.

  Polymers exhibiting pH-dependent water solubility are, for example, insoluble or sparingly soluble in acidic (pH 1-3) media such as gastric juice and weakly acidic to weakly alkaline (pH 5-8) such as intestinal fluid. Polymers having acidic dissociation groups that are soluble in media within any pH range are preferred. Examples of such a pH-dependent water-soluble polymer include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer (methacrylic acid-methyl acrylate) used as enteric coating agents. Copolymer, methacrylic acid-ethyl acrylate copolymer, etc., for example, Eudragit L100-55, L30D-55, L100, S100, FS (trade name, Rohm Pharma)) and the like. Two or more kinds of these polymers may be mixed and used at an appropriate ratio.

As a specific example of a polymer exhibiting water-solubility of delayed dissolution type, as a specific example of the polymer, 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, Nippon Soda) (Made by Co., Ltd.) (viscosity of 2 wt% 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 wt% aqueous solution at 20 ° C .: 150 -400 mPa · s), HPC-H (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C .: 1000-4000 mPa · s) and other hydroxypropylcellulose (HPC);
TC-5E (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: approx. 3 mPa · s), TC-5EW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C) SB-4 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: about 4 mPa · s), TC-5MW ( Product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2 wt% aqueous solution at 20 ° C: about 4.5 mPa · s) TC-5R (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 wt% at 20 ° C) Viscosity of aqueous solution: approx. 6 mPa · s), TC-5RW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C: approx. 6 mPa · s), TC-5S (trade name, Shin-Etsu) (Made by Chemical Industry Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 15 mPa · s), Metrose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C) : Approx. 50 mPa · s), Metro 65SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: approx. 50 mPa · s), Metrows 90SH-100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) ( Viscosity of 2 wt% aqueous solution at 20 ° C: approx. 100 mPa · s), Metrows 65SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 400 mPa · s), Metrows 90SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: about 400 mPa · s), Metrose 65SH-1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 Viscosity of 2 wt% aqueous solution at ℃: approx. 1500 mPa · s), Metrows 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 4000 mPa · s), Metrows 65SH -4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C: approx. 4000 mPa · s), Metroise 90SH-4 000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% by weight aqueous solution at 20 ° C: about 4000 mPa · s), Metroles 90SH-30000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (at 20 ° C Hydroxypropyl methylcellulose such as 2% aqueous solution viscosity: about 30000 mPa · s);
Metrows SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity: approx. 15 mPa · s, 2 wt% aqueous solution, 20 ° C), Metrows SM25 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2 at 20 ° C) Viscosity of weight% aqueous solution: approx. 25 mPa · s), Metrows SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2 wt% aqueous solution at 20 ° C: approx. 100 mPa · s), Metrows SM400 (trade name, Shin-Etsu) (Chemical Industry Co., Ltd.) (Viscosity of 2 wt% aqueous solution at 20 ° C: approx. 400 mPa · s), Metrows SM1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2 wt% aqueous solution at 20 ° C: approx. 1500mPa · s), Metrows SM4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C: approximately 4000mPa · s), Metrows SM8000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% by weight aqueous solution at 20 ° C .: about 8000 mPa · s)
WSR N-12K (trade name, manufactured by Union Carbide) (viscosity of 2 wt% aqueous solution at 20 ° C: 400 to 800 mPa · s), WSR N-60K (trade name, manufactured by Union Carbide) (2 weight at 20 ° C) % Aqueous solution viscosity: 2000-4000 mPa · s), WSR 301 (trade name, manufactured by Union Carbide) (1% aqueous solution viscosity at 25 ° C: 1500-4500 mPa · s), WSR Coagulant (trade name, Union Carbide) (Viscosity of 1 wt% aqueous solution at 25 ° C: 4500-7500 mPa · s), WSR 303 (trade name, manufactured by Union Carbide) (Viscosity of 1 wt% aqueous solution at 25 ° C: 70000 to 10,000 mPa · s), WSR Polyethylene oxide such as 308 (trade name, manufactured by Union Carbide) (viscosity of 1 wt% aqueous solution at 25 ° C .: 10000 to 15000 mPa · s);
Sunrose F-150MC (trade name, manufactured by Nippon Paper Industries Co., Ltd.) (viscosity of 1 wt% aqueous solution at 25 ° C: 1200-1800 mPa · s), Sunrose F-300MC (trade name, manufactured by Nippon Paper Industries Co., Ltd.) (at 25 ° C Viscosity of 1 wt% aqueous solution: 2500-3000 mPa · s), Sunrose F-1000MC (trade name, manufactured by Nippon Paper Industries Co., Ltd.) (viscosity of 1 wt% aqueous solution at 25 ° C: 8000-12000 mPa · s) ;
LH-11 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-21 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-31 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH- 22 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-32 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-20 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.), LH-30 ( Low-substituted hydroxypropylcellulose such as a trade name, manufactured by Shin-Etsu Chemical Co., Ltd.). Preferably, the polymer has a viscosity of 2% by weight aqueous solution at 20 ° C. or a viscosity of 1% by weight aqueous solution at 25 ° C. of 10 mPa · s or more. Two or more kinds of these polymers may be mixed and used at an appropriate ratio.

  Examples of the water-insoluble or poorly water-soluble polymer include block polymers and copolymers. A water-insoluble or hardly water-soluble polymer means a polymer having a water solubility at 37 ° C. of less than 0.1 mg / mL. For example, a fat-soluble base such as carnauba wax, hydrogenated castor oil, hydrogenated rapeseed oil, or polyglycerin; a composition in which at least one of the cellulose ester, acrylic polymer, polyvinyl acetate, polyvinyl chloride, and components is selected from the above polymers, or those 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). 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), for example Eudragit RS, RL (trade name, Rohm Pharma), a composition in which 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 a 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).

  In order to adjust the softening temperature of the polymer, a plasticizer may be added to the coating polymer. The softening temperature is an important factor for adjusting the mechanical properties of the polymer. Examples of suitable plasticizers are: 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 Although it is triethyl acid etc., it is not limited to them.

A core containing a physiologically active substance can be produced based on a conventional method known in the pharmaceutical technical field. The core can take the form of tablets, granules, fine granules, pellets, capsules, crystals, pastes, liquids, etc., but is not limited thereto.
The release of the physiologically active substance from the nucleus may be immediate release or sustained release in the absence of the coating layer. Here, “rapid release” refers to the start of the test when the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method) is carried out under the conditions of a paddle rotation speed of 50 rpm using 900 mL of an appropriate test solution. If the drug dissolution rate from the composition after 80 minutes is 80% or more, or the Japanese Pharmacopoeia dissolution test method 1 (rotating basket method) is used, the paddle rotation speed is 75 using an appropriate test solution 900 mL. It means that the drug dissolution rate from the composition is 30% or more after 30 minutes from the start of the test under the condition of rpm. “Sustained release” means that under the same conditions as described above, the Japanese Pharmacopoeia When the dissolution test method 2 (paddle method) or 1 (rotation basket method) is performed, the drug dissolution rate from the preparation 30 minutes after the start of the test is less than 80%. In addition, as the test solution, those commonly used in the field of pharmaceutical technology, for example, water, buffer solution 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, and the physiologically active substance is released from the nucleus by passive diffusion, the physiologically active substance is released when the nucleus is eroded, the environmental pH Those that release physiologically active substances in response to changes in the environment, those that expand the inside of the nucleus when environmental moisture is taken in and release the physiologically active substances at the internal pressure, those that release the physiologically active substance immediately upon disintegration or dissolution, etc. Any of these may be used.
Here, as the “composition from which the physiologically active substance is released from the composition by passive diffusion”, for example, a matrix composition using the above-described hydrophilic polymer (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, etc.) Products, matrix compositions using fat-soluble bases (for example, carnauba wax, hydrogenated castor oil, hydrogenated rapeseed oil, polyglycerin fatty acid ester, etc.), other release control bases (for example, cellulosic polymers such as ethyl cellulose; Examples thereof include matrix compositions using aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer suspension (acrylic 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 glycerides (eg, Gelucire 50/13 (trade name, manufactured by GATTEFOSSE)).
“Compositions that release physiologically active substances in response to changes in environmental pH” include, for example, enteric bases (eg, methacrylic acid copolymer L [Eudragit L (trade name, manufactured by Rohm Pharma)), methacrylic Matrix composition using 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)]. Such as things.
Examples of the “composition in which the inside of the composition expands by incorporating environmental moisture and releases a physiologically active substance by the internal pressure” include an 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 and molding a physiologically active substance and a pharmacologically acceptable carrier. It is done. Here, examples of the pharmacologically acceptable carrier include those described above. Further, mixing and molding are 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. The release mechanism of the physiologically active substance is preferably immediate release by disintegration or dissolution, that is, immediate release.

In addition to the production method described above, the nucleus containing the physiologically active substance is a highly dispersed, or dissolved, in an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles that are the center of the nucleus. Molecules (eg, hydroxypropylcellulose (eg, HPC-SL), hydroxypropylmethylcellulose (eg, TC-5-RW, TC-5-EW), low-substituted hydroxypropylcellulose (eg, L-HPC-32) Etc.), etc.) while spraying a physiologically active substance or a mixture of this with excipients (eg, mannitol, crystalline cellulose, etc.) and lubricants (eg, talc, light anhydrous silicic acid, etc.) in small amounts. Or as a suspension or spray or as a powder, rolling granulation method, pan coating method, fluidized bed coating method, melt granulation method and extrusion Malmo method It can also be prepared me. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 50 μm to about 1,500 μm are preferable.
Alternatively, for example, the above-mentioned excipients, disintegrants, binders or lubricants are added to the physiologically active substance, mixed (if necessary, further kneaded), and then compression-molded to prepare a tablet. You can also.

  If the physiologically active substance is weakly acidic to weakly alkaline and has relatively low water solubility, a pH adjuster or other solubilizing aid may be added in the same manner as described above for the purpose of adjusting the dissolution behavior from the composition. 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 physiologically active substance and the hydrophilic polymer is applied as the nucleus as it is. be able to.

The content of the physiologically active substance 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 a granule or a fine granule, 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 hydrophilic polymer content 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 release controlling composition of the present invention can take the form of tablets, granules, pellets, etc. depending on the form of the core, or may be a capsule containing them, but is not limited thereto. Not.
The membrane-coated release controlling composition of the present invention is obtained by coating the core obtained as described above with an aqueous dispersion or non-aqueous solution (hereinafter also referred to as “coating solution”) of the coating polymer and drying. Manufactured by. Alternatively, for example, it is also produced by compressing and molding a coating polymer around the core to form a coating layer using a method commonly used in the pharmaceutical technical field similar to the case of preparing multilayer tablets or dry-coated tablets. The
Examples of the method of coating the core with the coating liquid include a spray coating method.
The amount of the coating layer after drying is about 0.01 wt% to about 500 wt%, preferably about 0.1 wt% to about 300 wt%, more preferably about 1 wt% to about 200 wt%, relative to the core.
The thickness of the coating layer is about 1 μm to about 10 mm, preferably about 5 μm to about 5 mm.

As a solvent for the coating solution, water or an organic solvent can be used alone or a mixture of both can be used. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed liquid can be varied 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 organic solvents 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 and 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, for example, the coating solution can be carried out by spray coating the core by a fluidized bed coating method, a pan coating method or the like. it can. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as a lubricant. You may add as an agent.
After coating, an antistatic agent such as talc or light anhydrous silicic acid may be mixed as necessary.

  One or more ionic, nonionic, or polymeric surfactants may be added as a stabilizer to the coating solution. Examples of suitable surfactants are diethanolamine, fatty acids, hydroxypropylmethylcellulose, hydroxypropylcellulose, monoethanolamine, nonoxynol, octoxynol, oleic acid, poloxamer, polyoxyethylene 50 stearate, polyoxyfatty acid, polyoxyl hydrocarbon ether , Polysorbates (eg, polysorbate 80, etc.), povidone, fatty acid salts, sodium lauryl sulfate, sorbitan esters, 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 release controlling composition of the present invention corresponds to elution near the stomach in the initial stage after oral administration by coating the above-mentioned core containing the physiologically active substance with the above-described polymer using the above-mentioned method. Immediate acidic elution of the physiologically active substance at acidic pH (for example, pH 1 to 3) is suppressed, and after the small intestine, particularly weak acid to weak alkaline (for example, pH 5 to 8) corresponding to elution in the upper small intestine to the lower small intestine ), The elution of the physiologically active substance is sustained for a long time. In particular, elution at the initial stage after administration can be more strictly controlled by using a release controlling membrane.
Specifically, in the film-coated release controlling composition of the present invention,
1) 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) using 900 mL of the first solution of the Japanese Pharmacopoeia Disintegration Test The elution rate of physiologically active substances from is less than 10%,
2) In the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method, paddle rotation speed 50 rpm, 37 ° C) using 900 mL of the second liquid of the Japanese Pharmacopoeia Disintegration Test, the controlled release composition 24 hours after the start of the test The elution rate of physiologically active substances from the product is 40% or more.
In addition, specifically, the film-coated release controlling composition of the present invention includes (A) (1) formula:

(Wherein n represents an integer of 1 to 3, Ar represents an aromatic ring which may have a substituent) and a physiologically active substance which is a compound or a salt thereof and (2) hydroxypropylcellulose, A core containing a hydrophilic polymer selected from hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, (B) (1) cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate Enteric coating agent selected from succinate and methacrylic acid copolymer, (2) magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate and metake A lubricant selected from magnesium aluminate and (3) acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, mono and diacetylated monoglycerides, polyethylene glycol, A controlled release composition comprising 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) a hydrophilic polymer selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose, (3) lactose, sucrose, starch , Carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid and low-substituted hydroxypropyl cellulose, (4) magnesium stearate, calcium stearate, talc, light anhydrous silica Acid, colloidal silica, (5) Enteric coating agent selected from cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate and methacrylic acid copolymer, (6) α Binder selected from modified 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 A preferred specific example is a controlled release composition comprising a plasticizer selected from monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, mono and diacetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin and triethyl citrate. . (A) (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or (B) (1) a core comprising a salt thereof and a hydrophilic polymer selected from (2) hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, sodium carboxymethylcellulose and low-substituted hydroxypropylcellulose. 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 acid 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 Also, a preferred controlled example is a controlled release composition coated with a coating agent containing a plasticizer selected from triacetin and triethyl citrate.

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., particularly humans). In particular, it can be used as a therapeutic and prophylactic agent for the above-mentioned various diseases, preferably prostate cancer and breast cancer, etc., which can obtain a preventive and therapeutic effect by inhibiting steroid C _17,20 lyase.
The dosage of the membrane-coated controlled-release composition varies depending on the type of physiologically active substance, the subject of administration, the number of times of administration, etc., for example, when administered orally to an adult solid tumor patient (eg, 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 an effective amount of the physiologically active substance. It is.

The film-coated release controlling composition can further enhance the effect by using in combination with a physiologically active substance having other medicinal effects. As other physiologically active substances having other medicinal effects, those similar to the above-mentioned concomitant drugs are preferably exemplified. 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. 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, symptom, 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 with respect to 1 part by weight of the physiologically active substance described above.

The release control composition of the present invention (naked matrix composition) and the film-coated release control composition (hereinafter collectively referred to as “release control composition of the present invention”) are released as physiologically active substances. It can coat | cover with the coating layer whose property is quick release. The physiologically active substance may be the same as or different from the physiologically active substance contained in the controlled release composition of the present invention. In the case where they are different, the above combination drugs and the like are preferably exemplified as physiologically active substances.
With such a configuration, it is possible to impart fast drug dissolution in the initial stage after oral administration to the controlled release composition of the present invention.

  In addition, the controlled release composition of the present invention may be used in combination with one or more other controlled release compositions. In that case, it may be a single agent or a plurality of independent agents. It may be. Here, examples of the single agent include a single capsule encapsulating two or more types of controlled release compositions, and a multilayer tablet having a plurality of controlled release portions.

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 above compounds contained in the controlled release composition of the present invention. 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, it may be used for the purpose of an additive or synergistic effect of the medicinal effect or reduction of side effects. What becomes an agent is preferable. The active site may be the same or different, but a combination of physiologically active substances exhibiting the same medicinal effect, or the other physiologically active substance inhibits the inactivation factor to maintain the blood stability of the physiologically active substance A competing combination, or a combination that inhibits a metabolic factor with another physiologically active substance in order to avoid or delay metabolism of the physiologically active substance.
In addition, the release of the physiologically active substance contained in other controlled release compositions 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 like is also preferable.

Preferably, the physiologically active substance contained in the other controlled release composition is one that exhibits high water solubility under acidic conditions. Specifically, the solubility (Pharmaceutical 1 liquid, 37 ° C.) is 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 immediate elution of a physiologically active substance at an acidic pH (for example, pH 1 to 3) corresponding to elution in the vicinity of the stomach after oral administration, and the subsequent small intestine. Thereafter, elution of the physiologically active substance is continued for a long time, particularly in weakly acidic to weakly alkaline (eg, pH 5 to 8) corresponding to elution in the upper small intestine to the lower small intestine. 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, as the other controlled release composition, for example, immediately in the stomach to the vicinity of the duodenum Uniform drug elution / drug in the gastrointestinal tract by using a rapid-release composition to achieve elution and / or a timed release-type release control composition to improve dissolution in the vicinity of the large intestine Absorption can be realized.
That is, the present invention is a combination of the controlled release composition of the present invention and one or more other controlled release compositions containing the same physiologically active substance as the physiologically active substance contained in the controlled release composition of the present invention. The composition of the present invention (hereinafter also referred to as “mixed release control composition of the present invention”) has the following elution characteristics.
1) 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) using 900 mL of the first solution of the Japanese Pharmacopoeia Disintegration Test The elution rate of biologically active substances from the product is less than 10%. 2) Japanese Pharmacopoeia Dissolution Test Method 2 using the second solution 900 mL of the Japanese Pharmacopoeia Disintegration Test (Paddle method, paddle speed 50 rpm) 37 ° C.), the elution 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 is at least one other controlled release composition The release rate and release timing of the physiologically active substance in the material may be different. For example, it includes a time-release type release control composition using a release control film or the like, and includes a case where a physiologically active substance in a nucleus is eluted immediately after the film is disrupted or dissolved. Therefore, the other controlled release composition may be one in which a core containing a physiologically active substance is coated with a coating layer containing a polymer that exhibits pH-dependent or delayed dissolution type water solubility. Good. The same polymer as described above can be preferably used as the pH-dependent or delayed-type water-soluble polymer. For example, Eudragit L-100, S-100, FS (trade name, Rohm Pharma) Companies).

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 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.
In addition, as the hydroxypropylcellulose, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol 6000, red iron sesquioxide, and titanium oxide, the 14th revised Japanese Pharmacopoeia compatible product was used.

Comparative Example 1
Compound A, D-mannitol, low-substituted hydroxypropyl cellulose (L-HPC-11), hydroxypropyl cellulose (HPC-L), magnesium stearate, hydroxypropyl methylcellulose 2910 (TC-5), polyethylene glycol 8000, titanium oxide And about 300 mg each were weighed and tableted to obtain an immediate release tablet (Comparative Formulation 1) having a diameter of about 10 mm containing 100 mg of Compound A.
Compound A 100 mg
D-mannitol 133.5 mg
Low substituted hydroxypropylcellulose 42 mg
Hydroxypropylcellulose 6.5 mg
Magnesium stearate 3 mg
Hydroxypropyl methylcellulose 2910 10.416 mg
Polyethylene glycol 8000 2.1 mg
Titanium oxide 1.4 mg
Iron trioxide 0.084 mg

Reference Example 5
About 3.2 g of Compound A, about 6.4 g of hydroxypropyl methylcellulose (TC-5MW) and about 96 mg of magnesium stearate are mixed in powder, each about 303 mg is weighed, and the tableting pressure is 2.5 ton / cm ² and the diameter is 9 mm, 7.5 Tableted in the shape of R (formulation 1).

Reference Example 6
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 are mixed with powder, each about 303 mg is weighed, and the tableting pressure is 2.5 Tablets were formed into a shape of 9 mm in diameter and 7.5 R at ton / cm ² (Formulation 2).

Reference Example 7
About 3.2 g of Compound A, about 1.28 g of hydroxypropylmethylcellulose (Metroze 90SH-4000), about 5.12 g of polyethylene glycol (PEG6000) and about 96 mg of magnesium stearate are weighed and weighed about 303 mg each, and tableting pressure Tablets were formed into a shape of 2.5 ton / cm ² and a diameter of 9 mm and 7.5R (formulation 3).

Reference Example 8
The tablets obtained in Comparative Example 1 and Reference Examples 5 to 7 were coated as follows.
After 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, 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 methacrylic acid copolymer, was added to this solution to prepare a coating solution. Next, for the tablets obtained in Comparative Example 1 and Reference Examples 5 to 7 , using a high coater (manufactured by FREUND, HCT-MINI), the supply temperature is about 70 ° C., the drum rotation speed is 30 rpm, the spray pressure is about 0.1 MPa, Under the condition of a coating liquid injection rate of about 1.8 g / min, about 99 g of the coating liquid and about 15 g of the solid amount were coated on a total of about 300 g of tablets over about 1 hour. The increase in the weight 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)
Product 1: 4.265 g → 4.547 g (Formulation 5)
Product 2: 4.213 g → 4.529 g (Formulation 6)
Preparation 3: 4.225 g → 4.530 g (Formulation 7)
The formulation numbers of the coated tablets were formulation 4-7 as described above.

Reference example 1
Granules were prepared 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 resulting polymer dispersion to prepare a coating solution. About 1126 g of the coating solution containing Compound A prepared above (SPIR-A-FLOW) was coated on about 72 g of SELPHYR CP-305 as core particles. Coating conditions are: INLET temperature is about 60 ° C, spray pressure is about 1 kgf / cm ² , exhaust air scale 100, BED pressure is about 250 mmHg, rotor speed is about 300 rpm, spray injection speed is about 2-8 g / The spray position was at the bottom. After 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 to collect the granules remaining on the sieve, and vacuum dried at 40 ° C. for about 24 hours. The weight of the granule obtained after drying (Reference preparation 1) was about 170 g, and the content of Compound A was about 44.8% by weight of the granule.

Example 1
The granules obtained in Reference Example 1 were coated as follows.
About 3 g of triethyl citrate was dissolved in a mixed solution of about 388.8 g of ethanol and about 43.2 mL of purified water, and then 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 solution. About 70 g of Compound A-containing granules (Reference Formulation 1) obtained in Reference Example 1 were coated with about 331 g of the hydrophilic polymer-containing coating solution prepared above using a coating device (SPIR-A-FLOW). Coated. Coating conditions are INLET temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 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 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 to collect the granules remaining on the sieve, 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 2
The granules obtained in Reference Example 1 were coated as follows.
About 3 g of triethyl citrate was dissolved in about 388.8 g of ethanol and about 43.2 mL of purified water, and then 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 solution. About 70 g of Compound A-containing granules (Reference formulation 1) obtained in Reference Example 1 are coated with about 331 g of the hydrophilic polymer-containing coating solution prepared above using a coating device (SPIR-A-FLOW). did. Coating conditions are INLET temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 85-97, BED pressure of about 250 mmHg, rotor speed of about 150 rpm, spray injection speed of about 2-3 g / min, spray position at bottom. After 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 to collect the granules remaining on the sieve, 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 3
For the granules obtained in Reference Example 1 and Examples 1 and 2 , the mixing ratio of Reference Preparation 1 / Preparation 8 / Preparation 9 was 1/6/3 (as Compound A amount) so that the Compound A content was 100 mg. And mixed in No. 1 capsule to obtain Formulation 10.

Example 4
The granules obtained in Examples 1 and 2 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), and No. 3 capsules To obtain a preparation 11.

Reference 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 are powder-mixed. About 303 mg was weighed and tableted into a 9 mm diameter, 7.5R shape with a tableting pressure of 2.5 ton / cm ² to obtain Formulation 12.

Reference Example 10
The tablet obtained in Reference Example 9 was coated as follows.
After about 2.5 g of polyethylene glycol 6000 as a plasticizer and about 0.9 g of polysorbate 80 were dissolved in about 147 g of purified water, 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 methacrylic acid copolymer, was added to this solution to prepare a coating solution. Next, for formulation 12, using a high coater (manufactured by FREUND, HCT-MINI) under 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 speed of about 1.8 g / min. A total of about 300 g of tablets was coated with about 80 g as a coating solution and about 12.2 g as a solid amount over about 44 minutes. The increase in the weight of 10 tablets by the coating operation was from about 3.047 g to about 3.289 g, and it was confirmed that the coating component was covering the tablet surface, whereby Preparation 13 was obtained.

Reference Example 11
The tablet obtained in Reference Example 9 was coated as follows.
About 3.6 g of triethyl citrate as a plasticizer was dissolved in about 81 g of purified water, and then about 5.4 g of talc as a lubricant was uniformly dispersed. About 30 g of Eudragit RL-30D (trade name) and RS-30D (trade name), each of which is a solution of an aminoalkyl methacrylate copolymer, was added to this liquid to prepare a coating liquid. Next, for formulation 12, using a high coater (manufactured by 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 speed of about 1.8 g / min. A total of about 300 g of tablets was coated with about 60 g as a coating solution and about 10.8 g as a solid amount over about 33 minutes. The increase in the weight of 10 tablets by the coating operation was from about 3.042 g to about 3.228 g, and it was confirmed that the coating component was covering the tablet surface, whereby Preparation 14 was obtained.

Reference example 2
Granules were prepared as follows.
After dissolving about 7.2 g of mannitol in about 1176 mL of purified water, about 19.2 g of hydroxypropylcellulose (HPC-SL) was added and dispersed, and about 19.2 g of low-substituted hydroxypropylcellulose (L-HPC-32W) was added and dispersed. . About 120 g of Compound A was uniformly dispersed in the resulting polymer dispersion to prepare a coating solution. 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). Coating conditions are: inlet temperature of about 60 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 100, BED pressure of about 250 mmHg, rotor speed of about 100 rpm, spray injection speed of about 2-8 g / min The spray position was the lower side. After finishing the coating operation, the mixture was sieved with a 1180 μm sieve, and the passed granules were further sieved with a 710 μm sieve to collect the granules remaining on the sieve. The weight of the obtained granule (Reference preparation 2) was about 190 g, and the content of Compound A was about 49% by weight of the granule.

Reference example 3
Granules were prepared as follows.
Dissolve approximately 6.6 g of mannitol in approximately 607.2 mL of purified water, add and disperse approximately 17.6 g of hydroxypropyl methylcellulose (TC-5-EW), and add approximately 17.6 g of low-substituted hydroxypropylcellulose (L-HPC-32W). Distributed. About 110 g of compound A was uniformly dispersed in the resulting polymer dispersion to prepare a coating solution. About 72 g of SELFIA CP-507 as core particles was coated with about 725 g of the compound A-containing coating solution prepared above using a tumbling fluidized bed coating apparatus (SPIR-A-FLOW). Coating conditions are inlet temperature of about 60 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 100, BED pressure of about 300 mmHg, rotor speed of about 100 rpm, spray injection speed of about 8 g / min, The spray position was the lower side. After finishing the coating operation, the mixture was sieved with a 1180 μm sieve, and the passed granules were further sieved with a 710 μm sieve to collect the granules remaining on the sieve. The weight of the obtained granule (Reference preparation 3) was about 200 g.

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

Example 5
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 then 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 solution. About 170 g of the compound A-containing granule obtained in Reference Example 2 (Reference Formulation 2), about 900 g of the polymer-containing coating solution prepared above was used using a rolling fluidized bed coating apparatus (SPIR-A-FLOW). g was coated. Coating conditions are inlet temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 100, BED pressure of about 290 mmHg, rotor speed of about 100 rpm, spray injection speed of about 4-5 g / Min, the spray position was on the lower side. After finishing the coating operation, the mixture was sieved with a 1400 μm sieve, and the passed granules were further sieved with an 850 μm sieve to collect the granules remaining on the sieve. The weight of the obtained granule (Formulation 15) was about 237 g, and the drug content was about 32% by weight of the granule.

Example 6
About the granule obtained in Example 5 , the formulation 15 was enclosed in No. 3 capsule so that the compound A content might be 50 mg, and the formulation 16 was obtained.

Reference Example 12
The granules obtained in Reference Example 3 were coated as follows.
About 2.2 g of triethyl citrate was dissolved in a mixture of about 285.8 g of ethanol and about 31.8 mL of purified water, and then 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 solution. About 70 g of the compound A-containing granule (Reference formulation 3) obtained in Reference Example 3 is coated with the polymer-containing coating solution prepared above using a rolling fluidized bed coating apparatus (SPIR-A-FLOW). g was coated. Coating conditions are inlet temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 100, BED pressure of about 300 mmHg, rotor speed of about 100 rpm, spray injection speed of about 4-5 g / Min, the spray position was on the lower side. After finishing the coating operation, the mixture was sieved with a 1400 μm sieve, and the passed granules were further sieved with an 850 μm sieve to collect the granules remaining on the sieve. The weight of the obtained granule (Formulation 17) was about 85 g, and the drug content was about 33% by weight of the granule.

Reference Example 13
The granules obtained in Reference Example 4 were coated as follows.
About 2.2 g of triethyl citrate was dissolved in a mixture of about 285.8 g of ethanol and about 31.8 mL of purified water, and then 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 solution. About 70 g of the compound A-containing granule (Reference formulation 4) obtained in Reference Example 4 is applied to the polymer-containing coating solution prepared above using a rolling fluidized bed coating apparatus (SPIR-A-FLOW). g was coated. Coating conditions are inlet temperature of about 40 ° C, spray pressure of about 1 kgf / cm ² , exhaust air scale 100, BED pressure of about 300 mmHg, rotor speed of about 100 rpm, spray injection speed of about 4-5 g / Min, the spray position was on the lower side. After finishing the coating operation, the mixture was sieved with a 1400 μm sieve, and the passed granules were further sieved with an 850 μm sieve to collect the granules remaining on the sieve. The weight of the obtained granule (Formulation 18) was about 85 g, and the drug content was about 32% by weight of the granule.

Experimental example 1
The coated tablet (formulation 4) obtained in Reference Example 8 was orally administered to beagle dogs (male, body weight of about 10 kg), and the subsequent changes in plasma concentration of Compound A were examined. For comparison, the tablet obtained in Comparative Example 1 (Comparative preparation 1) was similarly orally administered to beagle dogs, and the subsequent plasma concentration transition of Compound A was examined. The result is shown in FIG.
As shown in FIG. 1, the blood concentration sustained physiologically active ingredient (compound A) were obtained by the control composition out release.

Experimental example 2
The coated tablets (formulations 5 to 7) obtained in Reference Example 8 were orally administered to beagle dogs (male, body weight of about 10 kg), and the changes in plasma concentration of Compound A thereafter were examined. The result is shown in FIG.
As shown in FIG. 2, the blood concentration sustained physiologically active ingredient (compound A) were obtained by the control composition out release.

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

Experimental Example 4
The capsule (preparation 11) obtained in Example 4 was orally administered to cynomolgus monkeys (male, body weight of about 4 kg), and the change in plasma concentration of Compound A thereafter was examined. The result is shown in FIG.
As shown in FIG. 4, the blood concentration persistence 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 Reference Examples 10 and 11 were orally administered to beagle dogs (male, body weight of about 10 kg), and the subsequent changes in plasma concentration of Compound A were examined. The result is shown in FIG.
As shown in FIG. 5, the blood concentration sustained physiologically active ingredient (compound A) were obtained by the control composition out release.

Experimental Example 6
The capsule obtained in Example 6 (Formulation 16) was orally administered to cynomolgus monkeys (male, body weight of about 4 kg), and the subsequent change in plasma concentration of Compound A was examined. The result is shown in FIG.
As shown in FIG. 6, the blood concentration persistence 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 steroid C _17,20 lyase inhibitory activity, whose blood concentration persistence is remarkably improved.

It is a figure which shows the time-dependent change of the plasma concentration of the bioactive substance after the oral administration of the film-coating-type controlled release composition of the present invention and the immediate-release tablet having no coating layer. It is a figure which shows the time-dependent change in the plasma concentration of the physiologically active substance after the oral administration of the dog of three types of the membrane-coated release control compositions of the present invention having nuclei containing different hydrophilic polymers. It is a figure which shows the time-dependent change of the plasma concentration of the bioactive substance after the dog oral administration of the mixed release control composition of this invention. It is a figure which shows a time-dependent change in the plasma concentration of the bioactive substance after monkey 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 bioactive 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 bioactive substance after the monkey oral administration of the release control composition of this invention.

Claims (5)

(A) (1) (+)-6- (7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or a salt thereof A physiologically active substance, and
(2) Nuclei containing hydroxypropylcellulose and low-substituted hydroxypropylcellulose as hydrophilic polymers (the nucleus is composed of (1) (+)-6- (7-hydroxy-6,7- Coated with a coating layer comprising dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl) -N-methyl-2-naphthamide or a salt thereof and (2) hydroxypropylcellulose and low substituted hydroxypropylcellulose )
(B) (1) a methacrylic acid copolymer selected from Eudragit L100 and Eudragit S100 ,
(2) Talc, and
(3) A controlled release composition for oral administration, which is coated with a coating layer containing a plasticizer selected from polyethylene glycol and triethyl citrate.   The controlled release composition according to claim 1, wherein the release of the physiologically active substance in the absence of the coating layer is immediate release.   The controlled release composition according to claim 1, wherein the content of the hydrophilic polymer is 3 wt% to 95 wt%.   The coating layer comprising the release controlling composition according to claim 1 containing a physiologically active substance that is the same as or different from the physiologically active substance contained in the release controlling composition, and the release of the physiologically active substance is immediate release. A controlled release composition comprising:   The controlled release composition according to claim 1, which is used for prevention or treatment of prostate cancer or breast cancer.

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