JPH1121241A - Solid preparation composition - Google Patents
Solid preparation compositionInfo
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- JPH1121241A JPH1121241A JP17863897A JP17863897A JPH1121241A JP H1121241 A JPH1121241 A JP H1121241A JP 17863897 A JP17863897 A JP 17863897A JP 17863897 A JP17863897 A JP 17863897A JP H1121241 A JPH1121241 A JP H1121241A
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、溶解性、消化管か
らの吸収等に優れた固形製剤組成物に関する。TECHNICAL FIELD The present invention relates to a solid pharmaceutical composition having excellent solubility, absorption from the digestive tract, and the like.
【０００２】[0002]
【従来の技術および発明が解決しようとする課題】特開
平４−１５４７６５号公報には、水利尿作用を有するバ
ソプレシン拮抗剤として有用な式（１）：BACKGROUND OF THE INVENTION JP-A-4-154765 discloses a compound of formula (1) useful as a vasopressin antagonist having an aquaretic effect.
【０００３】[0003]
【化１】 Embedded image
【０００４】で表される７−クロロ−５−ヒドロキシ−
１−［２−メチル−４−（２−メチルベンゾイルアミ
ノ）ベンゾイル］−２，３，４，５−テトラヒドロ−１
Ｈ−ベンゾアゼピンが開示されている。しかし、前記化
合物（１）を通常の製剤技術、例えば賦形剤などを加え
て顆粒剤や錠剤などの固形製剤に調製した場合には、消
化管からの吸収性が悪く、水利尿作用を十分に発揮させ
ることができない。[0004] 7-chloro-5-hydroxy-
1- [2-methyl-4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1
H-benzazepine is disclosed. However, when the compound (1) is prepared into a solid preparation such as a granule or a tablet by adding a conventional preparation technique, for example, an excipient or the like, the absorption from the digestive tract is poor, and the water diuretic effect is insufficient. Can not be demonstrated.
【０００５】そこで、本発明の目的は、前記化合物
（１）の溶解性を向上させることにより消化管からの薬
物の吸収が向上した固形製剤組成物を提供することであ
る。Accordingly, an object of the present invention is to provide a solid pharmaceutical composition having improved absorption of a drug from the digestive tract by improving the solubility of the compound (1).
【０００６】[0006]
【課題を解決するための手段】上記課題を解決するため
の本発明の固形製剤組成物は、前記一般式（１）で表さ
れる７−クロロ−５−ヒドロキシ−１−［２−メチル−
４−（２−メチルベンゾイルアミノ）ベンゾイル］−
２，３，４，５−テトラヒドロ−１Ｈ−ベンゾアゼピン
と、ヒドロキシプロピルセルロ−スとを含有した非晶質
な固形製剤組成物であることを特徴とする。Means for Solving the Problems The solid pharmaceutical composition of the present invention for solving the above-mentioned problems comprises a 7-chloro-5-hydroxy-1- [2-methyl-formula represented by the aforementioned general formula (1).
4- (2-methylbenzoylamino) benzoyl]-
It is an amorphous solid pharmaceutical composition containing 2,3,4,5-tetrahydro-1H-benzazepine and hydroxypropylcellulose.
【０００７】かかる非晶質な固形製剤組成物とすること
で、前記化合物（１）は、溶解性が向上し、消化管から
の薬物の吸収性が向上する。[0007] By forming such an amorphous solid pharmaceutical composition, the compound (1) has improved solubility and improved absorption of the drug from the digestive tract.
【０００８】[0008]
【発明の実施の形態】前記化合物（１）は、特開平４−
１５４７６５号公報に開示された合成方法によって得ら
れる。また前記ヒドロキシプロピルセルロ−スは、式
（２）：BEST MODE FOR CARRYING OUT THE INVENTION The compound (1) is disclosed in
It is obtained by the synthesis method disclosed in JP-A-154765. The hydroxypropyl cellulose is represented by the formula (2):
【０００９】[0009]
【化２】 Embedded image
【００１０】〔Ｒ1 、Ｒ2 およびＲ3 は水素原子または
基（ｉ）：[R 1 , R 2 and R 3 represent a hydrogen atom or a group (i):
【００１１】[0011]
【化３】 Embedded image
【００１２】（ｍは１以上の整数である。）である。ｎ
は繰り返し単位を示す。〕で表される。本発明の非晶質
な固形製剤組成物は、例えば下記に示す方法に従い製造
される。すなわち、所定量の前記化合物（１）とヒドロ
キシプロピルセルロ−スとを有機溶媒に溶解させた後、
有機溶媒を常法に従って留去することにより粉末として
得られる。(M is an integer of 1 or more). n
Represents a repeating unit. ] Is represented. The amorphous solid pharmaceutical composition of the present invention is produced, for example, according to the following method. That is, after dissolving a predetermined amount of the compound (1) and hydroxypropyl cellulose in an organic solvent,
It is obtained as a powder by removing the organic solvent by a conventional method.
【００１３】前記化合物（１）とヒドロキシプロピルセ
ルロ−スとの配合割合は、通常、前者に対して後者を重
量比で０．２〜２倍量程度、好ましくは０．２〜１倍程
度にするのが良く、特に好ましいのは０．２〜０．５倍
程度である。有機溶媒としては、前記化合物（１）およ
びヒドロキシプロピルセルロ−スを完全に溶解し得るも
のである限り特に制限はなく、従来公知のものをいずれ
も使用でき、具体的にはメタノ−ル、エタノ−ル、イソ
プロパノ−ル等の低級アルコ−ル類、アセトン、メチル
エチルケトン等のケトン類、ジクロロメタン、ジクロロ
エタン、クロロホルム、四塩化炭素等のハロゲン化炭化
水素類等やこれらの混合溶媒等を例示できる。また、必
要ならば水を添加しても良い。これらの有機溶媒の中で
も、低級アルコ−ル類とハロゲン化炭化水素類との混合
溶媒が、溶解性および溶媒留去などの面から好ましく、
具体的にはメタノ−ルもしくはエタノ−ルとジクロロメ
タンとの混合液があげられる。The compounding ratio of the compound (1) and hydroxypropyl cellulose is usually about 0.2 to 2 times, preferably about 0.2 to 1 times the weight of the former relative to the former. It is particularly preferable that the ratio is about 0.2 to 0.5 times. The organic solvent is not particularly limited as long as it can completely dissolve the compound (1) and hydroxypropyl cellulose, and any conventionally known organic solvent can be used. Specifically, methanol, ethanol and the like can be used. Examples thereof include lower alcohols such as toluene and isopropanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, and mixed solvents thereof. If necessary, water may be added. Among these organic solvents, a mixed solvent of a lower alcohol and a halogenated hydrocarbon is preferable from the viewpoint of solubility and solvent distillation, and the like.
Specific examples include a mixture of methanol or ethanol and dichloromethane.
【００１４】ヒドロキシプロピルセルロ−スとしては、
前記式（２）で表される化合物であれば特に制限はない
が、２％水溶液に調製した場合には、２０℃で通常、粘
度が２〜１０ｃｐｓ、好ましくは３〜６ｃｐｓの範囲に
あるのがよい。有機溶媒の留去方法としては、例えばエ
バポレ−ト法、噴霧乾燥法、流動層乾燥法等があげられ
るが、噴霧乾燥法が特に好適である。As hydroxypropyl cellulose,
There is no particular limitation as long as it is a compound represented by the formula (2), but when it is prepared as a 2% aqueous solution, the viscosity is usually in the range of 2 to 10 cps, preferably 3 to 6 cps at 20 ° C. Is good. Examples of the method for removing the organic solvent include an evaporating method, a spray drying method, and a fluidized bed drying method, and the spray drying method is particularly preferable.
【００１５】斯くして得られる固形製剤組成物に、必要
に応じて賦形剤、崩壊剤、結合剤、滑沢剤等を加え、常
法の製剤化方法により、散剤、細粒剤、顆粒剤、カプセ
ル剤、錠剤等の内服用固形製剤を調製することができ
る。上記賦形剤としては、例えば乳糖、白糖、デンプ
ン、結晶セルロース、ケイ酸などがあげられる。If necessary, excipients, disintegrants, binders, lubricants and the like are added to the solid preparation composition thus obtained, and powders, fine granules, granules are prepared by a conventional preparation method. Preparations for internal use such as preparations, capsules and tablets can be prepared. Examples of the excipient include lactose, sucrose, starch, crystalline cellulose, silicic acid and the like.
【００１６】結合剤としては、例えば水、エタノール、
デンプン液、メチルセルロース、ヒドロキシプロピルメ
チルセルロ−ス、ヒドロキシプロピルセルロ−スなどが
あげられる。崩壊剤としては、例えば低置換度ヒドロキ
シプロピルセルロース、カルボキシメチルセルロースカ
ルシウム、カルボキシスタ−チナトリウムなどがあげら
れる。As the binder, for example, water, ethanol,
Starch solution, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and the like can be mentioned. Examples of the disintegrant include low-substituted hydroxypropylcellulose, calcium carboxymethylcellulose, sodium carboxystatite and the like.
【００１７】滑沢剤としては、例えばタルク、ステアリ
ン酸塩などがあげられる。薬剤の投与方法としては特に
限定されないが、各種製剤形態、患者の年齢、性別、疾
患の状態、その他の条件に応じて従来公知の方法のなか
から適宜選択すればよい。本発明の固形製剤組成物に含
有されるべき前記化合物（１）の量としては、特に限定
されず広範囲から適宜選択されるが、通常、全重量に対
して約３０〜８０重量％、好ましくは約５０〜８０重量
％とするのがよい。Examples of the lubricant include talc, stearate and the like. The method of administering the drug is not particularly limited, and may be appropriately selected from conventionally known methods according to various preparation forms, patient age, gender, disease state, and other conditions. The amount of the compound (1) to be contained in the solid preparation composition of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 30 to 80% by weight, preferably about 30 to 80% by weight based on the total weight. It may be about 50-80% by weight.
【００１８】また投与単位形態の製剤中には、有効成分
となる前記化合物（１）が約１〜６０ｍｇの範囲で含有
されるのが好ましい。本発明固形製剤組成物の投与量
は、用法、患者の年齢、性別その他の条件、疾患の程度
等により適宜選択されるが、通常、一日当り有効成分と
なる前記化合物（１）の量が、体重１ｋｇ当り０．０２
〜２ｍｇ程度とするのが良い。It is preferable that the compound (1) as an active ingredient is contained in a dosage unit form in an amount of about 1 to 60 mg. The dose of the solid preparation composition of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like. Usually, the amount of the compound (1) serving as an active ingredient per day is as follows: 0.02 per kg of body weight
It is good to be about 2 mg.
【００１９】[0019]
【実施例】以下に、実施例および比較例をあげて本発明
を詳細に説明する。本発明の固形製剤組成物に使用する
７−クロロ−５−ヒドロキシ−１−［２−メチル−４−
（２−メチルベンゾイルアミノ）ベンゾイル］−２，
３，４，５−テトラヒドロ−１Ｈ−ベンゾアゼピン（以
下、主剤という。）の溶解性、および消化管からの吸収
性を調べるため、下記（ａ）〜（ｅ）に示す高分子と前
記主剤とを重量比１：１で含有する各粉末試料（実施例
１および比較例１〜６）を調製した。 （ａ）：ヒドロキシプロピルセルロ−ス（水溶性）[ 日
本曹達社製、HPC-SL] （ｂ）：ヒドロキシプロピルメチルセルロ−ス（水溶
性）[ 信越化学工業社製、TC-5E] （ｃ）：ポリビニルピロリドン（水溶性）[ 米国G.A.F.
社製、PVP K-30] （ｄ）：ヒドロキシプロピルメチルセルロ−スフタレー
ト（ｐＨ５．５以上で溶解） [信越化学工業社製 HP-5
5] （ｅ）：メタアクリル酸コポリマーＬ（ｐＨ６以上で溶
解） [レームファーマ社製、 Eudragit L100] 実施例１ 主剤１０ｇおよび高分子（ａ）１０ｇを、エタノ−ル６
０ｍｌとジクロロメタン１４０ｍｌとの混合溶媒に溶解
させ、スプレ−ドライ機（ＹＡＭＡＴＯ社製、型式ＧＢ
−２１）で噴霧乾燥して、粉末を調製した。 比較例１ 高分子（ａ）に代えて高分子（ｂ）を用いた以外は、実
施例１と同様の操作で粉末を調製した。 比較例２ 高分子（ａ）に代えて高分子（ｃ）を用いた以外は、実
施例１と同様の操作で粉末を調製した。 比較例３ 高分子（ａ）に代えて高分子（ｄ）を用いた以外は、実
施例１と同様の操作で粉末を調製した。 比較例４ 高分子（ａ）に代えて高分子（ｅ）を用いた以外は、実
施例１と同様の操作で粉末を調製した。 比較例５ 主剤８０ｇを気流式微粉砕機で粉砕することにより、約
２μｍの平均粒子径を有する粉末を調製した。 比較例６ 主剤１０ｇをエタノ−ル６０ｍｌとジクロロメタン１４
０ｍｌとの混合溶媒に溶解させ、実施例１と同様な操作
で粉末を調製した。 試験例１ （溶出試験１）上記調製した各粉末試料（実施例１およ
び比較例１〜６）について、日本薬局方溶出試験第２法
（パドル回転数：１００回転／分）に従い、溶出試験を
行った。溶出試験液および測定方法は以下の通りであ
る。The present invention will be described below in detail with reference to examples and comparative examples. 7-chloro-5-hydroxy-1- [2-methyl-4- used in the solid pharmaceutical composition of the present invention.
(2-methylbenzoylamino) benzoyl] -2,
In order to examine the solubility of 3,4,5-tetrahydro-1H-benzazepine (hereinafter referred to as the main agent) and the absorbability from the digestive tract, the following polymers (a) to (e) were used together with the main agent. Was prepared at a weight ratio of 1: 1 (Example 1 and Comparative Examples 1 to 6). (A): Hydroxypropyl cellulose (water-soluble) [Nippon Soda Co., Ltd., HPC-SL] (b): Hydroxypropyl methylcellulose (water-soluble) [Shin-Etsu Chemical Co., Ltd., TC-5E] (c ): Polyvinylpyrrolidone (water soluble) [US GAF
(PVP K-30, manufactured by Sharp Corporation) (d): Hydroxypropylmethylcellulose-sphthalate (dissolved at pH 5.5 or higher) [HP-5, manufactured by Shin-Etsu Chemical Co., Ltd.]
5] (e): Methacrylic acid copolymer L (dissolved at pH 6 or more) [Edragit L100, manufactured by Rohm Pharma Co., Ltd.] Example 1 10 g of the main agent and 10 g of the polymer (a) were mixed with ethanol 6
Dissolved in a mixed solvent of 0 ml and dichloromethane 140 ml, and spray-dried (Yamato, Model GB
The powder was prepared by spray drying in -21). Comparative Example 1 A powder was prepared in the same manner as in Example 1, except that the polymer (b) was used instead of the polymer (a). Comparative Example 2 A powder was prepared in the same manner as in Example 1, except that the polymer (c) was used instead of the polymer (a). Comparative Example 3 A powder was prepared in the same manner as in Example 1, except that the polymer (d) was used instead of the polymer (a). Comparative Example 4 A powder was prepared in the same manner as in Example 1, except that the polymer (e) was used instead of the polymer (a). Comparative Example 5 A powder having an average particle diameter of about 2 μm was prepared by pulverizing 80 g of the main agent with an airflow type pulverizer. Comparative Example 6 10 g of the main ingredient was mixed with 60 ml of ethanol and 14 ml of dichloromethane.
The powder was dissolved in a mixed solvent of 0 ml and a powder was prepared in the same manner as in Example 1. Test Example 1 (Dissolution Test 1) A dissolution test was performed on each of the powder samples prepared above (Example 1 and Comparative Examples 1 to 6) in accordance with the Japanese Pharmacopoeia Dissolution Test 2nd Method (paddle rotation speed: 100 rpm). went. The dissolution test solution and the measurement method are as follows.
【００２０】溶出試験溶液はラウリル硫酸ナトリウム
（和光純薬工業社製）０．２Ｗ／Ｖ％水溶液５００ｍｌ
を使用した。上記各粉末試料から、主剤５０ｍｇに対応
する量の粉末をそれぞれ精密に量り、上記溶出試験溶液
中に投入した。試験開始から５分、１０分、１５分、２
０分、３０分後の各粉末試料における主剤の溶出率
（％）を全自動溶出試験器（日本分光工業製ＤＴ−６１
０）を用いて測定した。The dissolution test solution was 500 ml of a 0.2 W / V% aqueous solution of sodium lauryl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.).
It was used. From each of the powder samples, an amount of powder corresponding to 50 mg of the main agent was precisely weighed and placed in the dissolution test solution. 5 minutes, 10 minutes, 15 minutes, 2
The dissolution rate (%) of the main agent in each powder sample after 0 minutes and 30 minutes was measured using a fully automatic dissolution tester (DT-61 manufactured by JASCO Corporation).
0).
【００２１】なお溶出率（％）は、主剤５０ｍｇをラウ
リル硫酸ナトリウム１Ｗ／Ｖ％水溶液５００ｍｌに溶解
させた溶液を標準溶液とし、この標準溶液および試料溶
液の波長２６５ｎｍと３３０ｎｍとにおける吸光度をセ
ル長１ｍｍの石英セルを用いて測定し、得られた吸光度
差の比によって求めた。その結果を表１に示す。The elution rate (%) is determined by measuring the absorbance at wavelengths of 265 nm and 330 nm of a solution obtained by dissolving 50 mg of the main agent in 500 ml of a 1 W / V% aqueous solution of sodium lauryl sulfate as a standard solution. It was measured using a 1 mm quartz cell and determined by the ratio of the obtained absorbance differences. Table 1 shows the results.
【００２２】[0022]
【表１】 [Table 1]
【００２３】表１から、主剤のみを噴霧乾燥して得られ
た比較例６は、比較例５に比べて主剤の溶出速度の向上
が確認されたが、主剤に高分子（ａ）を配合し噴霧乾燥
して得られた実施例１は、溶出速度がさらに速くなるこ
とが確認された。次に、上記各粉末試料（実施例１およ
び比較例１〜６）を用いた場合の、消化管からの薬物
（主剤）の吸収性を評価するために下記の試験を行っ
た。 試験例２ （薬物吸収試験）検体としてＳＤ系雄性ラット（７〜８
週齢）を使用した。各粉末試料を１％ヒドロキシプロピ
ルメチルセルロ−ス水溶液に懸濁させ、ラットの体重１
ｋｇ当たり主剤１０ｍｇに対応する量を経口ゾンデによ
り強制的に経口投与（ｎ＝３）した。From Table 1, it was confirmed that Comparative Example 6 obtained by spray-drying only the main agent improved the dissolution rate of the main agent as compared with Comparative Example 5, but the polymer (a) was added to the main agent. It was confirmed that the dissolution rate of Example 1 obtained by spray drying was further increased. Next, the following tests were performed to evaluate the absorption of the drug (main agent) from the digestive tract when each of the powder samples (Example 1 and Comparative Examples 1 to 6) was used. Test Example 2 (Drug absorption test) SD male rats (7-8
Weeks) was used. Each powder sample was suspended in a 1% aqueous solution of hydroxypropylmethylcellulose, and the weight of the rat was 1.
An amount corresponding to 10 mg of the main agent per kg was orally administered by an oral probe (n = 3).
【００２４】投与から０．５、１、２、４、６および８
時間後に軽度エ−テル麻酔下、ラットの大動脈から血液
を採取し、得られた血液を遠心分離（３０００ｒｐｍ，
１０分間）処理を行い、血清を得た。血清中の薬物（主
剤）濃度はｐ−ヒドロキシ安息香酸ｎ−ヘキシルを内部
標準物質として使用し、高速液体クロマトグラフィ−を
用いて定量した。 （高速液体クロマトグラフィー装置および測定条件） 装置：東ソ−製８０１０型システム 検出波長：２６５ｎｍ プレカラム：ＴＳＫ−ｐｒｅｃｏｌｕｍｎＢＳＡ・ＯＤ
Ｓ 分析カラム：ＶＹＤＡＣ Ｐｒｏｔｅｉｎ Ｐｅｐｔｉ
ｄｅ Ｃ18 移動相：アセトニトリル：５ｍＭＮａ2 ＳＯ4 （４：
６）、１％酢酸、０．３％ＴＨＦ 各粉末試料における薬物動態パラメ−タ−を表２に示
す。0.5, 1, 2, 4, 6, and 8 after administration
After time, under mild ether anesthesia, blood is collected from the aorta of the rat, and the obtained blood is centrifuged (3000 rpm,
(10 minutes), and serum was obtained. The drug (main agent) concentration in the serum was determined by high performance liquid chromatography using n-hexyl p-hydroxybenzoate as an internal standard. (High Performance Liquid Chromatography Apparatus and Measurement Conditions) Apparatus: 8010 system manufactured by Tosoh Corporation Detection wavelength: 265 nm Pre-column: TSK-precolumn BSA · OD
S Analysis column: VYDAC Protein Pepti
de C 18 mobile phase: acetonitrile: 5 mM Na 2 SO 4 (4:
6) Table 2 shows the pharmacokinetic parameters of each powder sample of 1% acetic acid and 0.3% THF.
【００２５】[0025]
【表２】 [Table 2]
【００２６】表２から、主剤にヒドロキシプロピルセル
ロ−ス（ａ）を配合し噴霧乾燥して得られた実施例１の
粉末試料は、比較例１〜６の粉末試料よりも高いＣmax
（最高血清中濃度）およびＡＵＣ（血清中濃度時間曲線
下面積）を示し、消化管からの主剤の吸収を高める効果
に優れていることが明らかになった。表１および表２の
結果から、主剤に配合する高分子としては前記ヒドロキ
シプロピルセルロ−ス（ａ）が最も好ましいことが明ら
かになった。 試験例３ （溶出試験２）主剤とヒドロキシプロピルセルロ−ス
（ａ）との配合割合を変えた粉末試料（実施例２〜４）
をそれぞれ調製し、それらの粉末試料について上述の試
験例１と同様にして溶出試験を行った。 実施例２ 主剤２０ｇおよびヒドロキシプロピルセルロ−ス（前出
（ａ））４ｇをエタノ−ル７２ｍｌとジクロロメタン１
６８ｍｌとの混合溶媒に溶解させ、スプレ−ドライ機
（前出）で噴霧乾燥して、粉末を調製した。 実施例３ 主剤２０ｇおよびヒドロキシプロピルセルロ−ス１０ｇ
をエタノ−ル９０ｍｌとジクロロメタン２１０ｍｌとの
混合溶媒に溶解させ、スプレ−ドライ機（前出）で噴霧
乾燥して、粉末を調製した。 実施例４ 主剤１０ｇおよびヒドロキシプロピルセルロ−ス２０ｇ
をエタノ−ル９０ｍｌとジクロロメタン２１０ｍｌとの
混合溶媒に溶解させ、スプレ−ドライ機（前出）で噴霧
乾燥して、粉末を調製した。From Table 2, it can be seen that the powder sample of Example 1 obtained by blending hydroxypropyl cellulose (a) with the base material and spray drying has a higher C max than the powder samples of Comparative Examples 1 to 6.
(Maximum serum concentration) and AUC (area under the serum concentration time curve), and it was revealed that it was excellent in the effect of increasing the absorption of the main agent from the digestive tract. From the results in Tables 1 and 2, it was clarified that the above-mentioned hydroxypropyl cellulose (a) was most preferable as the polymer to be blended in the main ingredient. Test Example 3 (Dissolution test 2) Powder sample in which the mixing ratio of the main agent and hydroxypropyl cellulose (a) was changed (Examples 2 to 4)
Were prepared, and a dissolution test was performed on those powder samples in the same manner as in Test Example 1 described above. Example 2 20 g of the main ingredient and 4 g of hydroxypropyl cellulose (mentioned above (a)) were added to 72 ml of ethanol and 1 ml of dichloromethane.
The powder was dissolved in a mixed solvent of 68 ml and spray-dried with a spray-dryer (described above) to prepare a powder. Example 3 20 g of main ingredient and 10 g of hydroxypropyl cellulose
Was dissolved in a mixed solvent of 90 ml of ethanol and 210 ml of dichloromethane, and spray-dried with a spray-dryer (described above) to prepare a powder. Example 4 10 g of main ingredient and 20 g of hydroxypropyl cellulose
Was dissolved in a mixed solvent of 90 ml of ethanol and 210 ml of dichloromethane, and spray-dried with a spray-dryer (described above) to prepare a powder.
【００２７】これらの各実施例の溶出試験結果を上述の
実施例１および比較例５、６の試験結果と共に、表３に
示す。The results of the dissolution test of each of these examples are shown in Table 3 together with the test results of Example 1 and Comparative Examples 5 and 6 described above.
【００２８】[0028]
【表３】 [Table 3]
【００２９】表３から、比較例５、６に比べて実施例１
〜４の粉末試料を用いた場合には、主剤の溶出率が大き
く向上することが明らかになった。とりわけ実施例１〜
４の粉末試料のうち、主剤に対してヒドロキシプロピル
セルロ−スを重量比で０．２〜０．５倍程度配合した実
施例２および３では、溶出速度がより速くなっているこ
とがわかる。From Table 3, it can be seen that Example 1 was compared with Comparative Examples 5 and 6.
When the powder samples of Nos. To 4 were used, it was found that the dissolution rate of the main agent was greatly improved. In particular, Examples 1 to
It can be seen that, among the powder samples of Examples 4, in Examples 2 and 3 in which hydroxypropyl cellulose was blended about 0.2 to 0.5 times by weight with respect to the main ingredient, the dissolution rate was higher.
【００３０】[0030]
【発明の効果】本発明の固形製剤組成物は、主剤の溶解
性を改善することにより消化管からの主剤の吸収性が向
上したものである。従って、本発明は水利尿作用を十分
に発揮するバソプレシン拮抗剤として有用なものと考え
られる。Industrial Applicability The solid pharmaceutical composition of the present invention has improved absorption of the main agent from the digestive tract by improving the solubility of the main agent. Therefore, the present invention is considered to be useful as a vasopressin antagonist sufficiently exerting an aquaretic effect.
Claims (1)
メチル−４−（２−メチルベンゾイルアミノ）ベンゾイ
ル］−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾア
ゼピンと、ヒドロキシプロピルセルロ−スとを含有した
非晶質な固形製剤組成物。(1) 7-chloro-5-hydroxy-1- [2-
Methyl-4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine and hydroxypropylcellulose.
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| JP17863897A JP4210355B2 (en) | 1997-07-03 | 1997-07-03 | Solid pharmaceutical composition |
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| JP4210355B2 JP4210355B2 (en) | 2009-01-14 |
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ID=16051966
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| JP17863897A Expired - Lifetime JP4210355B2 (en) | 1997-07-03 | 1997-07-03 | Solid pharmaceutical composition |
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