JP4210355B2 - Solid pharmaceutical composition - Google Patents
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- JP4210355B2 JP4210355B2 JP17863897A JP17863897A JP4210355B2 JP 4210355 B2 JP4210355 B2 JP 4210355B2 JP 17863897 A JP17863897 A JP 17863897A JP 17863897 A JP17863897 A JP 17863897A JP 4210355 B2 JP4210355 B2 JP 4210355B2
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Description
【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。
【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）：
【０００３】
【化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。
【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。
【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非晶質な固形製剤組成物は、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、２％水溶液に調製したときの２０℃での粘度が３〜６ｃｐｓである水溶性ヒドロキシプロピルセルロースとを、重量比１：０．５の割合で、有機溶媒に溶解させた後、前記有機溶媒を留去し、粉末化することにより得られることを特徴とする。
【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。
【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ースは、式（２）：
【０００９】
【化２】
〔Ｒ1 、Ｒ2 およびＲ3 は水素原子または基（ｉ）：
【００１１】
【化３】
（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、２％水溶液に調製したときの２０℃での粘度が３〜６ｃｐｓである水溶性のヒドロキシプロピルセルロースである。
本発明の非晶質な固形製剤組成物は、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）と前記ヒドロキシプロピルセルロー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。
【００１３】
前記化合物（１）とヒドロキシプロピルセルロースとの配合割合は、通常、前者に対して後者を重量比で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ー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、具体的にはメタノール、エタノール、イソプロパノール等の低級アルコール類、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、低級アルコー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、具体的にはメタノールもしくはエタノールとジクロロメタンとの混合液があげられる。
【００１４】
ヒドロキシプロピルセルロースとしては、前記式（２）で表される化合物であって、２％水溶液に調製したときに、２０℃で、粘度が３〜６ｃｐｓの範囲にあるものが挙げられる。
有機溶媒の留去方法としては、例えばエバポレート法、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。
【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。
【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ース、ヒドロキシプロピルセルロー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、カルボキシスターチナトリウムなどがあげられる。
【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。
【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。
【００１９】
【実施例】
以下に、実施例、比較例、および参考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（参考例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ース（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ース（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ースフタレート（ｐＨ５．５以上で溶解）［信越化学工業社製、ＨＰ−５５］
（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］
参考例１
主剤１０ｇおよび高分子（ａ）１０ｇを、エタノール６０ｍｌとジクロロメタン１４０ｍｌとの混合溶媒に溶解させ、スプレードライ機（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、参考例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、参考例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、参考例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、参考例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をエタノール６０ｍｌとジクロロメタン１４０ｍｌとの混合溶媒に溶解させ、参考例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（参考例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。
【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、２０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−６１０）を用いて測定した。
【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。
【００２２】
【表１】
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参考例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（参考例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ース水溶液に懸濁させ、ラットの体重１ｋｇ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。
【００２４】
投与から０．５、１、２、４、６および８時間後に、軽度エーテル麻酔下で、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ーを用いて定量した。
（高速液体クロマトグラフィー装置および測定条件）
装置：東ソー製８０１０型システム
検出波長：２６５ｎｍ
プレカラム：ＴＳＫ−ｐｒｅｃｏｌｕｍｎＢＳＡ・ＯＤＳ
分析カラム：ＶＹＤＡＣ Ｐｒｏｔｅｉｎ Ｐｅｐｔｉｄｅ Ｃ１８
移動相：アセトニトリル：５ｍＭ Ｎａ２ＳＯ４（４：６）、１％酢酸、０．３％ＴＨＦ
各粉末試料における薬物動態パラメーターを表２に示す。
【００２５】
【表２】
表２から、主剤にヒドロキシプロピルセルロース（ａ）を配合し噴霧乾燥して得られた参考例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ース（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ース（ａ）との配合割合を変えた粉末試料（実施例１、参考例２〜３）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。
参考例２
主剤２０ｇおよびヒドロキシプロピルセルロース（前出（ａ））４ｇをエタノール７２ｍｌとジクロロメタン１６８ｍｌとの混合溶媒に溶解させ、スプレードライ機（前出）で噴霧乾燥して、粉末を調製した。
実施例１
主剤２０ｇおよびヒドロキシプロピルセルロース１０ｇをエタノール９０ｍｌとジクロロメタン２１０ｍｌとの混合溶媒に溶解させ、スプレードライ機（前出）で噴霧乾燥して、粉末を調製した。
参考例３
主剤１０ｇおよびヒドロキシプロピルセルロース２０ｇをエタノール９０ｍｌとジクロロメタン２１０ｍｌとの混合溶媒に溶解させ、スプレードライ機（前出）で噴霧乾燥して、粉末を調製した。
【００２７】
これらの実施例および参考例の溶出試験結果を上述の参考例１および比較例５、６の試験結果と共に、表３に示す。
【００２８】
【表３】
表３から、比較例５、６に比べて、実施例１、および参考例１〜３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、および参考例１〜２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ースを重量比で０．５倍程度配合した実施例１では、溶出速度がより速くなっていることがわかる。
【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。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a solid preparation composition excellent in solubility, absorption from the digestive tract, and the like.
[0002]
[Background Art and Problems to be Solved by the Invention]
JP-A-4-154765 discloses a formula (1) useful as a vasopressin antagonist having a water diuretic action:
[0003]
[Chemical 1]
7-chloro-5-hydroxy-1- [2-methyl-4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzoazepine represented by the formula .
However, when the compound (1) is prepared into a solid preparation such as a granule or a tablet by adding an ordinary formulation technique, for example, excipient, etc., the absorbability from the gastrointestinal tract is poor and the water diuretic action is sufficient. Cannot be demonstrated.
[0005]
Accordingly, an object of the present invention is to provide a solid pharmaceutical composition in which the absorption of the drug from the digestive tract is improved by improving the solubility of the compound (1).
[0006]
[Means for Solving the Problems]
The amorphous solid pharmaceutical composition of the present invention for solving the above-mentioned problems is a 7-chloro-5-hydroxy-1- [2-methyl-4- (2-) represented by the general formula (1). Methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzoazepine and water-soluble hydroxypropylcellulose having a viscosity of 3-6 cps at 20 ° C. when prepared in a 2% aqueous solution, It is obtained by dissolving in an organic solvent at a weight ratio of 1: 0.5 and then distilling off the organic solvent to form a powder .
[0007]
By using such an amorphous solid pharmaceutical composition, the compound (1) has improved solubility and improved drug absorption from the gastrointestinal tract.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
The compound (1) can be obtained by the synthesis method disclosed in JP-A-4-154765.
Also, the hydroxypropyl cellulose chromatography scan of the formula (2):
[0009]
[Chemical formula 2]
[R 1 , R 2 and R 3 are hydrogen atoms or groups (i):
[0011]
[Chemical 3]
(M is an integer greater than or equal to 1). n represents a repeating unit. It is a water-soluble hydroxypropyl cellulose having a viscosity of 3 to 6 cps at 20 ° C. when prepared in a 2% aqueous solution.
Amorphous solid preparation composition of the present invention can be prepared according to the method shown below SL.
That is, a predetermined amount of the compound (1) and the hydroxypropylcellulose are dissolved in an organic solvent, and then the organic solvent is distilled off according to a conventional method to obtain a powder.
[0013]
The compounding ratio of the compound (1) and hydroxypropyl cellulose is usually about 0.5 times the weight of the latter with respect to the former.
The organic solvent is not particularly limited as long as it can completely dissolve the compound (1) and hydroxypropylcellulose, and any conventionally known one can be used, specifically, methanol, ethanol, isopropanol, etc. Examples include lower alcohols, 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 lower alcohols and halogenated hydrocarbons is preferable from the viewpoints of solubility and solvent distillation, and specific examples include methanol or a mixed solution of ethanol and dichloromethane. .
[0014]
Examples of hydroxypropylcellulose include compounds represented by the above formula (2), which have a viscosity in the range of 3 to 6 cps at 20 ° C. when prepared in a 2% aqueous solution.
Examples of the method for distilling off the organic solvent include an evaporation method, a spray drying method, a fluidized bed drying method, and the like, and the spray drying method is particularly preferable.
[0015]
To the solid preparation composition thus obtained, excipients, disintegrants, binders, lubricants and the like are added as necessary, and powders, fine granules, granules, capsules are prepared by conventional formulation methods. A solid preparation for internal use such as an agent or a tablet can be prepared.
Examples of the excipient include lactose, sucrose, starch, crystalline cellulose, and silicic acid.
[0016]
As the binder, for example, water, ethanol, starch solution, methylcellulose, hydroxypropyl methyl cellulose chromatography scan, such as hydroxypropylcellulose over scan and the like.
As the disintegrating agent, for example, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, etc. Karubokishisuta over sodium Chi and the like.
[0017]
Examples of the lubricant include talc and stearate.
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, sex, disease state, and other conditions.
The amount of the compound (1) to be contained in the solid pharmaceutical composition of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 30 to 80% by weight, preferably about 30% by weight based on the total weight. It should be about 50-80% by weight.
[0018]
Moreover, it is preferable that the said compound (1) used as an active ingredient is contained in the dosage unit form formulation in the range of about 1-60 mg.
The dose of the solid pharmaceutical composition of the present invention is appropriately selected depending on the usage, patient age, sex and other conditions, the degree of disease, etc. Usually, the amount of the compound (1) that becomes an active ingredient per day is It is good to be about 0.02 to 2 mg per kg body weight.
[0019]
【Example】
Hereinafter, the present invention will be described in detail with reference to Examples , Comparative Examples , and Reference Examples .
7-Chloro-5-hydroxy-1- [2-methyl-4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzo used in the solid pharmaceutical composition of the present invention In order to investigate the solubility of azepine (hereinafter referred to as the main agent) and the absorbability from the digestive tract, each powder containing the polymer shown in the following (a) to (e) and the main agent in a weight ratio of 1: 1. Samples ( Reference Example 1 and Comparative Examples 1 to 6) were prepared.
(A): Hydroxypropyl cellulose (water-soluble) [Nippon Soda Co., Ltd., HPC-SL]
(B): Hydroxypropyl methylcellulose (water-soluble) [manufactured by Shin-Etsu Chemical Co., Ltd., TC-5E]
(C): Polyvinylpyrrolidone (water-soluble) [US G. A. F. PVP K-30]
(D): Hydroxypropyl methylcellulose phthalate (dissolved at pH 5.5 or more) [manufactured by Shin-Etsu Chemical Co., Ltd., HP-55]
(E): Methacrylic acid copolymer L (dissolved at pH 6 or more) [manufactured by Rohm Pharma, Eudragit L100]
Reference example 1
10 g of the main agent and 10 g of the polymer (a) were dissolved in a mixed solvent of 60 ml of ethanol and 140 ml of dichloromethane, and spray-dried with a spray dryer (type GB-21 manufactured by YAMATO) to prepare a powder.
Comparative Example 1
A powder was prepared in the same manner as in Reference 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 Reference 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 Reference 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 Reference 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 fine pulverizer.
Comparative Example 6
The main agent 10g was dissolved in a mixed solvent of ethanol 60ml of dichloromethane 140 ml, to prepare Powder a similar operation as in Reference Example 1.
Test example 1
(Dissolution test 1)
About each prepared powder sample ( Reference example 1 and Comparative Examples 1-6), the elution test was done according to Japanese Pharmacopoeia elution test 2nd method (paddle rotation speed: 100 rotations / min). The dissolution test solution and measurement method are as follows.
[0020]
As a dissolution test solution, sodium lauryl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) 0.2 W / V% aqueous solution 500 ml was used.
From each of the powder samples, an amount of powder corresponding to 50 mg of the main agent was precisely weighed and put into the dissolution test solution. The dissolution rate (%) of the main agent in each powder sample after 5 minutes, 10 minutes, 15 minutes, 20 minutes and 30 minutes from the start of the test was measured using a fully automatic dissolution tester (DT-610 manufactured by JASCO Corporation). .
[0021]
The elution rate (%) was obtained by using a solution obtained by dissolving 50 mg of the main agent in 500 ml of a 1 W / V% sodium lauryl sulfate solution as a standard solution, and the absorbance of the standard solution and the sample solution at wavelengths of 265 nm and 330 nm with quartz having a cell length of 1 mm. It measured using the cell and calculated | required by ratio of the obtained absorbance difference. The results are shown in Table 1.
[0022]
[Table 1]
From Table 1, it was confirmed that Comparative Example 6 obtained by spray-drying only the main agent showed an improvement in the elution rate of the main agent as compared with Comparative Example 5. However, the polymer (a) was added to the main agent and spray-dried. In Reference Example 1 obtained as above, it was confirmed that the elution rate was further increased.
Next, in order to evaluate the absorbability of the drug (main agent) from the gastrointestinal tract when each of the above powder samples ( Reference Example 1 and Comparative Examples 1 to 6) was used, the following test was performed.
Test example 2
(Drug absorption test)
SD male rats (7-8 weeks old) were used as specimens. Each powder sample was suspended in a 1% hydroxypropylmethylcellulose aqueous solution, and an amount corresponding to 10 mg of the main agent per 1 kg body weight of the rat was forcibly orally administered (n = 3) with an oral sonde.
[0024]
In 1, 2, 4, 6 and 8 hours after administration, under mild et chromatography ether anesthesia, blood was collected from the aorta of a rat, the blood obtained by centrifugation (3000 rpm, 10 min) treatment Serum was obtained. Drug in serum (main agent) concentration using p- hydroxy-benzoic acid n- hexyl as an internal standard substance was quantified by high performance liquid chromatography.
(High-performance liquid chromatography equipment and measurement conditions)
Apparatus: Tosoh over steel 8010 type system Detection wavelength: 265 nm
Precolumn: TSK-precolumnBSA / ODS
Analytical column: VYDAC Protein Peptide C 18
Mobile phase: Acetonitrile: 5 mM Na 2 SO 4 (4: 6), 1% acetic acid, 0.3% THF
Pharmacokinetic parameters over in each powder sample is shown in Table 2.
[0025]
[Table 2]
From Table 2, the powder sample of Reference Example 1 obtained by blending hydroxypropylcellulose (a) into the main agent and spray-drying has a higher C max (maximum serum concentration) than the powder samples of Comparative Examples 1-6 and AUC (area under the serum concentration time curve) was shown, and it was revealed that the effect of enhancing the absorption of the main agent from the gastrointestinal tract was excellent.
From the results of Tables 1 and 2, it was revealed that the hydroxypropyl cellulose (a) is most preferable as a polymer to be blended in the main agent.
Test example 3
(Dissolution test 2)
Powder samples (Example 1, Reference Examples 2 to 3 ) with different blending ratios of the main agent and hydroxypropyl cellulose (a) were prepared, respectively, and the dissolution test was performed on those powder samples in the same manner as in Test Example 1 described above. went.
Reference example 2
20 g of the main agent and 4 g of hydroxypropylcellulose (supra (a)) were dissolved in a mixed solvent of 72 ml of ethanol and 168 ml of dichloromethane and spray-dried with a spray dryer (supra) to prepare a powder.
Example 1
20 g of the main agent and 10 g of hydroxypropylcellulose were 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.
Reference example 3
10 g of the main agent and 20 g of hydroxypropylcellulose were 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]
The dissolution test results for these real施例and reference examples with the test results of Reference Example 1 and Comparative Examples 5 and 6 described above, are shown in Table 3.
[0028]
[Table 3]
From Table 3, compared with Comparative Examples 5 and 6, in the case of using the powder samples of Example 1, and Reference Examples 1 to 3, it was revealed that the dissolution rate of the base resin is greatly improved.
Especially Example 1, and of the powder sample of Reference Example 1-2, Example 1 was blended 0.5 times in a weight ratio of hydroxypropyl cellulose against base resin, that the dissolution rate becomes faster Recognize.
[0030]
【The invention's effect】
The solid preparation composition of the present invention has improved absorbability of the main agent from the digestive tract by improving the solubility of the main agent.
Therefore, it is considered that the present invention is useful as a vasopressin antagonist that sufficiently exerts a diuretic action.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17863897A JP4210355B2 (en) | 1997-07-03 | 1997-07-03 | Solid pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17863897A JP4210355B2 (en) | 1997-07-03 | 1997-07-03 | Solid pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1121241A JPH1121241A (en) | 1999-01-26 |
| JP4210355B2 true JP4210355B2 (en) | 2009-01-14 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17863897A Expired - Lifetime JP4210355B2 (en) | 1997-07-03 | 1997-07-03 | Solid pharmaceutical composition |
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| Country | Link |
|---|---|
| JP (1) | JP4210355B2 (en) |
Cited By (2)
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| WO2014104412A1 (en) | 2012-12-28 | 2014-07-03 | Otsuka Pharmaceutical Co., Ltd. | Injectable depot formulation comprising optically active tolvaptan and process of producing the same |
| WO2015056805A1 (en) | 2013-10-15 | 2015-04-23 | Otsuka Pharmaceutical Co., Ltd. | Drug for preventing and/or treating polycystic kidney disease |
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| TWI405574B (en) * | 2007-06-21 | 2013-08-21 | Otsuka Pharma Co Ltd | Pharmaceutical solid preparation and production method thereof |
| TWI459947B (en) | 2007-06-26 | 2014-11-11 | Otsuka Pharma Co Ltd | Benzazepine compound and pharmaceutical preparation |
| CN102293734A (en) * | 2010-06-25 | 2011-12-28 | 江苏恒瑞医药股份有限公司 | Tolvaptan solid dispersion and preparation method thereof |
| CN102406622B (en) * | 2011-11-16 | 2017-02-08 | 浙江华海药业股份有限公司 | Tolvaptan solid preparation |
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| JP2018024628A (en) * | 2016-08-02 | 2018-02-15 | ニプロ株式会社 | Amorphous solid dispersion containing tolvaptan and method for producing the same |
| KR20200074046A (en) * | 2018-12-14 | 2020-06-24 | 명인제약주식회사 | A pharmaceutical composition for preparing solid dispersion comprising tolvaptan and method for preparing the same |
| CN111888335A (en) * | 2020-08-21 | 2020-11-06 | 福安药业集团重庆礼邦药物开发有限公司 | Tolvaptan pharmaceutical solid preparation and preparation method thereof |
-
1997
- 1997-07-03 JP JP17863897A patent/JP4210355B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014104412A1 (en) | 2012-12-28 | 2014-07-03 | Otsuka Pharmaceutical Co., Ltd. | Injectable depot formulation comprising optically active tolvaptan and process of producing the same |
| US9597283B2 (en) | 2012-12-28 | 2017-03-21 | Otsuka Pharmaceutical Co., Ltd. | Injectable depot formulation comprising optically active tolvaptan and process of producing the same |
| WO2015056805A1 (en) | 2013-10-15 | 2015-04-23 | Otsuka Pharmaceutical Co., Ltd. | Drug for preventing and/or treating polycystic kidney disease |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH1121241A (en) | 1999-01-26 |
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