JPH1135460A - Pharmaceutical preparation containing dibenzo(b,e)oxepin derivative - Google Patents
Pharmaceutical preparation containing dibenzo(b,e)oxepin derivativeInfo
- Publication number
- JPH1135460A JPH1135460A JP19842797A JP19842797A JPH1135460A JP H1135460 A JPH1135460 A JP H1135460A JP 19842797 A JP19842797 A JP 19842797A JP 19842797 A JP19842797 A JP 19842797A JP H1135460 A JPH1135460 A JP H1135460A
- Authority
- JP
- Japan
- Prior art keywords
- cellulose
- dibenzo
- derivative
- oxepin
- pharmaceutical preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pyrane Compounds (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、ジベンゾ〔b,e〕
オキセピン誘導体を含有し、長期間安定で、アレルギー
疾患または皮膚疾患に対する経口剤として有用な医薬品
製剤に関する。TECHNICAL FIELD The present invention relates to dibenzo [b, e]
The present invention relates to a pharmaceutical preparation containing an oxepin derivative, which is stable for a long time and is useful as an oral preparation for allergic diseases or skin diseases.
【０００２】[0002]
【従来の技術】本発明のジベンゾ〔b,e〕オキセピン誘
導体は、抗アレルギー作用および抗炎症作用を示し、鼻
アレルギーや喘息等のアレルギー疾患、蕁麻疹等の皮膚
疾患に有用であることが報告されている（特開昭６３−
１０７８４号公報）。しかしながら、本発明のジベンゾ
〔b,e〕オキセピン誘導体は、経口投与用の医薬品製剤
の製造に多用される賦形剤、崩壊剤、結合剤および滑沢
剤等の添加物の添加により保存時に経時的に分解される
ため、安定な経口投与用の医薬品製剤の開発が嘱望され
ていた。BACKGROUND OF THE INVENTION The dibenzo [b, e] oxepin derivative of the present invention exhibits an antiallergic action and an antiinflammatory action, and is reported to be useful for allergic diseases such as nasal allergy and asthma, and skin diseases such as urticaria. (Japanese Unexamined Patent Publication No.
No. 10784). However, the dibenzo [b, e] oxepin derivative of the present invention can be used over time during storage due to the addition of additives such as excipients, disintegrants, binders and lubricants that are frequently used in the production of pharmaceutical preparations for oral administration. Therefore, development of a stable pharmaceutical preparation for oral administration has been desired.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は、ジベ
ンゾ〔b,e〕オキセピン誘導体を含有する安定で有効な
経口投与用の医薬品製剤を提供することにある。An object of the present invention is to provide a stable and effective pharmaceutical preparation for oral administration containing a dibenzo [b, e] oxepin derivative.
【０００４】[0004]
【課題を解決するための手段】本発明によれば、式
（Ｉ）According to the present invention, there is provided a compound of formula (I)
【０００５】[0005]
【化２】 Embedded image
【０００６】［式中、Ａは、単結合、-CH=CH-または-(C
H2)n-（ｎは１〜３の整数を表す）を表し、R1およびR2
は同一または異なって水素、低級アルキル、または一緒
になってＮをはさんで形成される複素環基を表す］で表
されるジベンゾ〔b,e〕オキセピン誘導体またはその薬
理学的に許容される塩、糖、セルロースおよびセルロー
ス誘導体を含有することを特徴とする医薬品製剤が提供
される。Wherein A is a single bond, -CH = CH- or-(C
H 2 ) n- (n represents an integer of 1 to 3), and R 1 and R 2
Represents the same or different hydrogen, lower alkyl, or a heterocyclic group formed together by N.] or a pharmaceutically acceptable dibenzo [b, e] oxepin derivative Pharmaceutical formulations are provided that contain salts, sugars, cellulose and cellulose derivatives.
【０００７】[0007]
【発明の実施の形態】以下、式（Ｉ）で表されるジベン
ゾ〔b,e〕オキセピン誘導体を化合物（Ｉ）とする。式
（Ｉ）の各基の定義において、低級アルキルは炭素数１
〜６の直鎖状もしくは分枝状のアルキル、例えばメチ
ル、エチル、プロピル、イソプロピル、ブチル、イソブ
チル、tert-ブチル、ペンチル、ヘキシル等を包含す
る。Ｎをはさんで形成される複素環基は、ピロリジニ
ル、モルホリノ、チオモルホリノ、Ｎ−メチルピペラジ
ニル、ピラゾリジニル、ピペリジノ、ピペラジニル、イ
ンドリル、イソインドリル等を包含する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a dibenzo [b, e] oxepin derivative represented by the formula (I) is referred to as a compound (I). In the definition of each group of the formula (I), lower alkyl has 1 carbon atom.
-6 linear or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Heterocyclic groups formed across N include pyrrolidinyl, morpholino, thiomorpholino, N-methylpiperazinyl, pyrazolidinyl, piperidino, piperazinyl, indolyl, isoindolyl and the like.
【０００８】化合物（Ｉ）の薬理学的に許容される塩と
しては、塩酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸
塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩
等の有機酸塩があげられ、薬理学的に許容される金属塩
としては、ナトリウム塩、カリウム塩等のアルカリ金属
塩、マグネシウム塩、カルシウム塩等のアルカリ土類金
属塩のほか、アルミニウム塩、亜鉛塩もあげられ、薬理
学的に許容される有機アミン付加塩としては、モルホリ
ン、ピペリジン等の付加塩、薬理学的に許容されるアミ
ノ酸付加塩としては、リジン、グリシン、フェニルアラ
ニン等の付加塩があげられる。The pharmacologically acceptable salts of the compound (I) include inorganic salts such as hydrochloride, sulfate, phosphate, acetate, maleate, fumarate, tartrate, and citric acid. Organic salts such as salts are exemplified. Examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, and aluminum salt. And pharmacologically acceptable organic amine addition salts such as morpholine and piperidine, and pharmaceutically acceptable amino acid addition salts such as lysine, glycine and phenylalanine. Salt.
【０００９】本医薬品製剤としては、式（Ｉ）のうち、
ＡがCH2であり、R1およびR2がともにCH3である化合物を
含有することがより好ましい。本発明で使用される化合
物（Ｉ）は、特開昭６３−１０７８４号公報に開示され
た方法あるいはそれに準じて製造することができる。そ
れら化合物の具体例としてThe pharmaceutical preparation of the formula (I)
More preferably, it contains a compound wherein A is CH 2 and R 1 and R 2 are both CH 3 . Compound (I) used in the present invention can be produced by the method disclosed in JP-A-63-10784 or a method analogous thereto. As specific examples of those compounds
【００１０】[0010]
【化３】 Embedded image
【００１１】で表される(Ｚ)-11-(3-ジメチルアミノプ
ロピリデン)-6,11-ジヒドロジベンゾ〔b,e〕オキセピン
-2-酢酸塩酸塩（化合物１）があげられる。その理化学
的性質は、以下に示すとおりである。1 H-NMR(270MHz, DMSO-d6) δ(ppm);約11(2H, br), 7.5-
7.2(4H, m), 7.09(1H, dd, J=8.1, 2.2), 7.07(1H, d,
J=2.2), 6.79(1H, d, J=8.1), 5.65(1H, t, J=7.1), 5.
18(2H, br), 3.54(2H, s), 3.24(2H, br dd, J=8.4, 7.
0), 2.77(2H, brdt, J=約8, 約7), 2.72(6H, s) MS(FAB)(m/z): 338.17(M+H-HCl)+ 以下に、本発明について詳細に説明する。(Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] oxepin
2-acetate hydrochloride (compound 1). Its physicochemical properties are as shown below. 1 H-NMR (270 MHz, DMSO-d 6 ) δ (ppm); about 11 (2H, br), 7.5-
7.2 (4H, m), 7.09 (1H, dd, J = 8.1, 2.2), 7.07 (1H, d,
J = 2.2), 6.79 (1H, d, J = 8.1), 5.65 (1H, t, J = 7.1), 5.
18 (2H, br), 3.54 (2H, s), 3.24 (2H, br dd, J = 8.4, 7.
0), 2.77 (2H, brdt , J = about 8, about 7), 2.72 (6H, s ) MS (FAB) (m / z): 338.17 (M + H-HCl) + Hereinafter, the present invention details Will be described.
【００１２】化合物（Ｉ）またはその薬理学的に許容さ
れる塩を含有する経口投与用の医薬品製剤は、以下の方
法に従って製造することができる。すなわち、化合物
（Ｉ）またはその薬理学的に許容される塩、医薬品添加
物として許容される糖、セルロース、セルロース誘導
体、必要に応じ通常使用される、賦形剤、崩壊剤、結合
剤、滑沢剤およびその他所望に応じ医薬品添加物として
許容される添加物を混合した後、常法に従い製剤化する
ことにより製造することができる。A pharmaceutical preparation for oral administration containing Compound (I) or a pharmacologically acceptable salt thereof can be produced according to the following method. That is, compound (I) or a pharmacologically acceptable salt thereof, a sugar, a cellulose, a cellulose derivative acceptable as a pharmaceutical additive, an excipient, a disintegrant, a binder, a lubricant, which is ordinarily used as necessary. It can be produced by mixing a powder and other additives that are acceptable as pharmaceutical additives as required, and then formulating the mixture according to a conventional method.
【００１３】本発明の医薬品製剤の製造において使用す
る糖としては、例えば、蔗糖または乳糖等、好ましくは
乳糖を使用し、セルロースとしては例えば、結晶セルロ
ースを使用し、セルロース誘導体としては例えばクロス
カルメロースナトリウム、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、カルボキシ
メチルセルロースカルシウム等、好ましくはクロスカル
メロースナトリウムを使用する。The sugar used in the preparation of the pharmaceutical preparation of the present invention is, for example, sucrose or lactose, preferably lactose, the cellulose is, for example, crystalline cellulose, and the cellulose derivative is, for example, croscarmellose. Sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, etc., preferably croscarmellose sodium are used.
【００１４】本発明の医薬品製剤の製造においては、上
記糖、セルロース、セルロース誘導体を賦形剤、崩壊剤
および結合剤として使用することができるが、さらに所
望に応じ、これらに医薬品の添加物として許容される添
加物を添加することができる。賦形剤としては例えば澱
粉もしくは澱粉誘導体である小麦澱粉、米澱粉、トウモ
ロコシ澱粉、馬鈴薯澱粉、α化澱粉、部分α化澱粉、カ
ルボキシメチルデンプン、デキストリン、プルラン、ヒ
ドロキシプロピルスターチ等、その他ポリビニルピロリ
ドン、ステアリン酸アルミニウム、アラビアゴム、寒
天、マクロゴール、トラガント等を使用することができ
るが、これらは賦形剤としてばかりでなく崩壊剤または
結合剤として用いることもできる。In the preparation of the pharmaceutical preparation of the present invention, the above-mentioned sugar, cellulose and cellulose derivative can be used as excipients, disintegrants and binders. Acceptable additives can be added. Examples of the excipients include starch or starch derivatives such as wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, carboxymethyl starch, dextrin, pullulan, hydroxypropyl starch and the like, and other polyvinylpyrrolidone, Aluminum stearate, gum arabic, agar, macrogol, tragacanth and the like can be used, but they can be used not only as excipients but also as disintegrants or binders.
【００１５】さらに、滑沢剤としては、ステアリン酸、
ステアリン酸カルシウム、ステアリン酸マグネシウム、
ステアリン酸ポリオキシル４０、タルク、セタノール、
ラブリワックス、無水ケイ酸、パラフィン、ホウ酸、ロ
イシン、ポリオキシエチレン脂肪酸エステル、安息香酸
ナトリウム等を使用することができる。ジベンゾ〔b,
e〕オキセピン誘導体またはその薬理的に許容される塩
の含有率は、１製剤あたり０．０１〜５０％、好ましく
は０．１〜１０％、さらに好ましくは０．５〜５％であ
る。糖の含有率は、１製剤あたり１〜９９％、好ましく
は１０〜９０％、さらに好ましくは３０〜７０％であ
る。セルロースの含有率は、１〜９９％、好ましくは１
０から５０％、さらに好ましくは２０〜４０％である。
セルロース誘導体の含有率は、１製剤あたり、０．１〜
５０％、好ましくは０．５〜１０％、さらに好ましくは
１〜５％である。Further, as a lubricant, stearic acid,
Calcium stearate, magnesium stearate,
Polyoxyl stearate 40, talc, cetanol,
Lovely wax, silicic anhydride, paraffin, boric acid, leucine, polyoxyethylene fatty acid ester, sodium benzoate and the like can be used. Dibenzo [b,
e] The content of the oxepin derivative or a pharmaceutically acceptable salt thereof is 0.01 to 50%, preferably 0.1 to 10%, more preferably 0.5 to 5% per preparation. The content of sugar is 1-99%, preferably 10-90%, more preferably 30-70% per preparation. The content of cellulose is 1 to 99%, preferably 1 to 99%.
It is 0 to 50%, more preferably 20 to 40%.
The content of the cellulose derivative is 0.1 to 0.1 per preparation.
It is 50%, preferably 0.5 to 10%, more preferably 1 to 5%.
【００１６】本発明の医薬品製剤の製造においては、上
記糖、セルロース、セルロース誘導体として、各々乳
糖、結晶セルロース、クロスカルメロースナトリウムを
使用することが好ましい。本発明の医薬品製造には、錠
剤、顆粒剤、カプセル剤、ドライシロップ剤および細粒
剤等が含まれる。これらの製剤は適量の化合物（Ｉ）、
医薬品添加物として許容される糖、セルロース、セルロ
ース誘導体および必要に応じて使用される、賦形剤、崩
壊剤、結合剤、滑沢剤および所望に応じその他医薬品添
加物として許容される添加物を混合した後、常法に従
い、製剤化することにより製造することができる。本製
剤の製造法は、一般的に良く使用されている方法ならば
特に限定されない。すなわち、混合された添加物および
ジベンゾ〔b,e〕オキセピン誘導体を乾式や湿式の方法
で粒状とする方法、具体的には、スプレードライヤー、
乾式造粒機、押し出し型造粒機、流動層造粒乾燥機、攪
拌造粒機、または攪拌流動乾燥造粒機などがあげられ
る。また、一旦乾式や湿式の方法で粒状としたものを打
錠機あるいは成形物を得る方法によって打錠成形する方
法、混合された添加物およびジベンゾ〔b,e〕オキセピ
ン誘導体を直接打錠する方法、一旦乾式や湿式の方法で
粒状としたものをカプセルに充填する方法および混合さ
れた添加物およびジベンゾ〔b,e〕オキセピン誘導体を
直接カプセル充填する方法などがあげられる。また、上
記方法によって得られた錠剤等医薬品製剤に各種の皮膜
などをコーティングすることも可能である。In the preparation of the pharmaceutical preparation of the present invention, it is preferable to use lactose, crystalline cellulose and croscarmellose sodium as the sugar, cellulose and cellulose derivative, respectively. The pharmaceutical preparation of the present invention includes tablets, granules, capsules, dry syrups, fine granules and the like. These preparations contain an appropriate amount of compound (I),
Sugars, celluloses, cellulose derivatives and, if necessary, excipients, disintegrants, binders, lubricants and other additives acceptable as pharmaceutical excipients which are acceptable as excipients. After mixing, it can be manufactured by formulating according to a conventional method. The method for producing the present preparation is not particularly limited as long as it is a commonly used method. That is, a method of granulating the mixed additive and the dibenzo [b, e] oxepin derivative by a dry or wet method, specifically, a spray dryer,
Examples include a dry granulator, an extrusion granulator, a fluidized-bed granulator / dryer, a stirring granulator, and a stirring fluidized-dry granulator. Also, a method in which granules once granulated by a dry or wet method are tableted by a tableting machine or a method of obtaining a molded product, and a method in which mixed additives and dibenzo [b, e] oxepin derivatives are directly compressed. Examples of the method include a method of filling granules once obtained by a dry or wet method into capsules, and a method of directly filling capsules with a mixed additive and a dibenzo [b, e] oxepin derivative. It is also possible to coat the pharmaceutical preparations such as tablets obtained by the above method with various films.
【００１７】本発明を以下の実施例および比較例でさら
に詳しく説明する。The present invention will be described in more detail with reference to the following Examples and Comparative Examples.
【００１８】[0018]
実施例１ 化合物１、乳糖（ＤＭＶ製、２００Ｍ）、結晶セルロー
ス（旭化成製、アビセル）、クロスカルメロースナトリ
ウム（ＦＭＣ製、Ac-di-sol）を流動層造粒機（フロイ
ント製）内に仕込み、ポリビニルアルコール（日本合成
化学製、ゴーセノールEG-05）水溶液を添加しながら造
粒し、乾燥工程を経て造粒物を得た。Example 1 Compound 1, lactose (manufactured by DMV, 200M), crystalline cellulose (manufactured by Asahi Kasei, Avicel), and croscarmellose sodium (manufactured by FMC, Ac-di-sol) were charged in a fluidized bed granulator (manufactured by Freund). Then, granulation was performed while adding an aqueous solution of polyvinyl alcohol (Gosenol EG-05, manufactured by Nippon Synthetic Chemical Industry), and a granulated product was obtained through a drying step.
【００１９】造粒物にステアリン酸マグネシウム（堺化
学製）を加えて混合後、ロータリー型打錠機（菊水製作
所製）を用い圧縮成形した。成形条件は錠剤重量１９０
ｍｇ［化合物１含量０．９５ｍｇ（０．５重量％）］、
金型は８ｍｍφ二段Ｒ型とし、錠剤を得た。この時のク
ロスカルメロースナトリウムの量を１．０重量％にし、
上記方法により１９０ｍｇの錠剤を得た。Magnesium stearate (manufactured by Sakai Chemical) was added to the granules, mixed, and then compression molded using a rotary tableting machine (manufactured by Kikusui Seisakusho). The molding conditions were 190 tablet weight.
mg [Compound 1 content 0.95 mg (0.5% by weight)],
The mold was an 8 mmφ two-stage R type to obtain tablets. The amount of croscarmellose sodium at this time was adjusted to 1.0% by weight,
190 mg tablets were obtained by the above method.
【００２０】実施例２ 実施例１のクロスカルメロースナトリウムの量を５．０
重量％にし、実施例１と同様の方法により１９０ｍｇの
錠剤を得た。実施例１および実施例２の処方を第１表に
示す。Example 2 The amount of croscarmellose sodium of Example 1 was adjusted to 5.0.
In the same manner as in Example 1, 190 mg of tablets were obtained. Table 1 shows the formulations of Examples 1 and 2.
【００２１】[0021]
【表１】 [Table 1]
【００２２】実施例３ 実施例１における化合物１の量を１．０重量％とし、ク
ロスカルメロースナトリウムの量を１．０重量％にし、
実施例１と同様の方法により１９０ｍｇの錠剤を得た。Example 3 The amount of compound 1 in Example 1 was 1.0% by weight, the amount of croscarmellose sodium was 1.0% by weight,
A tablet of 190 mg was obtained in the same manner as in Example 1.
【００２３】実施例４ 実施例１における化合物１の量を１．０重量％とし、ク
ロスカルメロースナトリウムの量を５．０重量％にし、
実施例１と同様の方法により１９０ｍｇの錠剤を得た。
実施例３および実施例４の処方を第２表に示す。Example 4 The amount of compound 1 in Example 1 was 1.0% by weight and the amount of croscarmellose sodium was 5.0% by weight.
A tablet of 190 mg was obtained in the same manner as in Example 1.
Table 2 shows the formulations of Examples 3 and 4.
【００２４】[0024]
【表２】 [Table 2]
【００２５】実施例５ 実施例１における化合物１の量を２．０重量％とし、ク
ロスカルメロースナトリウムの量を１．０重量％にし、
実施例１と同様の方法により１９０ｍｇの錠剤を得た。Example 5 The amount of compound 1 in Example 1 was 2.0% by weight, the amount of croscarmellose sodium was 1.0% by weight,
A tablet of 190 mg was obtained in the same manner as in Example 1.
【００２６】実施例６ 実施例１における化合物１の量を２．０重量％とし、ク
ロスカルメロースナトリウムの量を５．０重量％にし、
実施例１と同様の方法により１９０ｍｇの錠剤を得た。
実施例５および実施例６の処方を第３表に示す。Example 6 The amount of compound 1 in Example 1 was 2.0% by weight, the amount of croscarmellose sodium was 5.0% by weight,
A tablet of 190 mg was obtained in the same manner as in Example 1.
Table 3 shows the formulations of Example 5 and Example 6.
【００２７】[0027]
【表３】 [Table 3]
【００２８】実施例７ 実施例１における化合物１の量を５．０重量％とし、ク
ロスカルメロースナトリウムの量を１．０重量％にし、
実施例１と同様の方法により１９０ｍｇの錠剤を得た。Example 7 The amount of compound 1 in Example 1 was adjusted to 5.0% by weight and the amount of croscarmellose sodium was adjusted to 1.0% by weight.
A tablet of 190 mg was obtained in the same manner as in Example 1.
【００２９】実施例８ 実施例１の化合物１の量を５．０重量％とし、クロスカ
ルメロースナトリウムの量を５．０重量％にし、実施例
１と同様の方法により１９０ｍｇの錠剤を得た。実施例
７および実施例８の処方を第４表に示す。Example 8 A 190 mg tablet was obtained in the same manner as in Example 1, except that the amount of compound 1 in Example 1 was 5.0% by weight and the amount of croscarmellose sodium was 5.0% by weight. . Table 4 shows the formulations of Examples 7 and 8.
【００３０】[0030]
【表４】 [Table 4]
【００３１】比較例１ 実施例１のクロスカルメロースナトリウムを乳糖と結晶
セルロースに置き換え、実施例１と同様の方法により１
９０ｍｇの錠剤を得た。比較例１の処方を第５表に示
す。Comparative Example 1 Lactose and crystalline cellulose were used in place of croscarmellose sodium of Example 1, and 1 was prepared in the same manner as in Example 1.
90 mg tablets were obtained. Table 5 shows the formulation of Comparative Example 1.
【００３２】[0032]
【表５】 [Table 5]
【００３３】比較例２ 実施例３のクロスカルメロースナトリウムを乳糖と結晶
セルロースに置き換え、実施例１と同様の方法により１
９０ｍｇの錠剤を得た。比較例２の処方を第６表に示
す。Comparative Example 2 The same procedure as in Example 1 was repeated except that croscarmellose sodium of Example 3 was replaced with lactose and crystalline cellulose.
90 mg tablets were obtained. Table 6 shows the formulation of Comparative Example 2.
【００３４】[0034]
【表６】 [Table 6]
【００３５】試験例１ 安定性試験−加速試験 実施例１〜８および参考例１、２で得られた錠剤につい
て安定性試験−加速試験［４０℃−７５％ＲＨ、６ヶ
月；安定性ガイドライン（厚生省薬務局通知、薬新薬第
３０号、平成６年４月２１日）］を実施し、その化合物
１の残存率を評価した。その結果を第７表に示す。Test Example 1 Stability test-Accelerated test Stability test-Accelerated test [40 ° C.-75% RH, 6 months; stability guideline for tablets obtained in Examples 1 to 8 and Reference Examples 1 and 2; Notification of Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuhin Shinyaku No. 30, April 21, 1994)], and the residual ratio of Compound 1 was evaluated. Table 7 shows the results.
【００３６】[0036]
【表７】 [Table 7]
【００３７】実施例に示した乳糖および結晶セルロース
をベースとした処方にクロスカルメロースを添加した処
方は、保存安定性試験後の化合物１の残存率が高かっ
た。これに対し、比較例に示すクロスカルメロースナト
リウムを添加していない錠剤の保存安定性は、添加した
錠剤に比して、化合物１の残存率が低かった。以上の結
果より、乳糖および結晶セルロースをベースとした処方
にクロスカルメロースナトリウム等のセルロース誘導体
を添加した処方は、安定なジベンゾ〔b,e〕オキセピン
誘導体を含有する製剤を提供することを見出した。The formulation containing croscarmellose added to the formulation based on lactose and crystalline cellulose shown in the Examples had a high residual ratio of Compound 1 after the storage stability test. On the other hand, the storage stability of the tablet to which no croscarmellose sodium was added as shown in Comparative Example was lower than that of the tablet to which the croscarmellose sodium was added. From the above results, it was found that a formulation in which a cellulose derivative such as croscarmellose sodium was added to a formulation based on lactose and crystalline cellulose provided a formulation containing a stable dibenzo [b, e] oxepin derivative. .
【００３８】[0038]
【発明の効果】本発明によれば、有効成分としてジベン
ゾ〔b,e〕オキセピン誘導体を含有する長期間安定に存
在する医薬品製剤を提供することができる。According to the present invention, it is possible to provide a long-term stable pharmaceutical preparation containing a dibenzo [b, e] oxepin derivative as an active ingredient.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 47/26 Ａ６１Ｋ 47/26 Ｂ 47/38 47/38 Ｂ // Ｃ０７Ｄ 313/12 Ｃ０７Ｄ 313/12 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code FI A61K 47/26 A61K 47/26 B 47/38 47/38 B // C07D 313/12 C07D 313/12
Claims (6)
１〜３の整数を表す）を表し、R1およびR2は同一または
異なって水素、低級アルキル、または一緒になってＮを
はさんで形成される複素環基を表す］で表されるジベン
ゾ〔b,e〕オキセピン誘導体またはその薬理学的に許容
される塩、糖、セルロースおよびセルロース誘導体を含
有することを特徴とする医薬品製剤。1. A compound of the formula (I) [Wherein, A represents a single bond, -CH = CH- or-(CH 2 ) n- (n represents an integer of 1 to 3), and R 1 and R 2 are the same or different and are hydrogen, lower Alkyl, or a heterocyclic group formed by putting N together.] Or a pharmacologically acceptable salt, sugar, cellulose and cellulose derivative thereof represented by the formula: Pharmaceutical preparation characterized by containing.
〔b,e〕オキセピン誘導体を含有する医薬品製剤。2. The pharmaceutical preparation containing the dibenzo [b, e] oxepin derivative according to claim 1, wherein the sugar is lactose.
項１記載のジベンゾ〔b,e〕オキセピン誘導体を含有す
る医薬品製剤。3. The pharmaceutical preparation containing a dibenzo [b, e] oxepin derivative according to claim 1, wherein the cellulose is crystalline cellulose.
ナトリウム、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またはカルボキシメチルセ
ルロースカルシウムである請求項１記載のジベンゾ〔b,
e〕オキセピン誘導体を含有する医薬品製剤。4. The cellulose derivative is croscarmellose sodium, low-substituted hydroxypropylcellulose,
The dibenzo [b, a carboxymethylcellulose or calcium carboxymethylcellulose according to claim 1,
e] Pharmaceutical preparations containing oxepin derivatives.
ロースであり、セルロース誘導体がクロスカルメロース
ナトリウム、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またはカルボキシメチルセ
ルロースカルシウムである請求項１記載のジベンゾ〔b,
e〕オキセピン誘導体を含有する医薬品製剤。5. The sugar is lactose, the cellulose is crystalline cellulose, and the cellulose derivative is croscarmellose sodium, low-substituted hydroxypropylcellulose,
The dibenzo [b, a carboxymethylcellulose or calcium carboxymethylcellulose according to claim 1,
e] Pharmaceutical preparations containing oxepin derivatives.
ゾ〔b,e〕オキセピン誘導体を含有する医薬品製剤。6. A pharmaceutical preparation containing the dibenzo [b, e] oxepin derivative according to claim 1, which is for oral administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19842797A JP3828247B2 (en) | 1997-07-24 | 1997-07-24 | Pharmaceutical preparations containing dibenzo [b, e] oxepin derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19842797A JP3828247B2 (en) | 1997-07-24 | 1997-07-24 | Pharmaceutical preparations containing dibenzo [b, e] oxepin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1135460A true JPH1135460A (en) | 1999-02-09 |
| JP3828247B2 JP3828247B2 (en) | 2006-10-04 |
Family
ID=16390921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19842797A Expired - Lifetime JP3828247B2 (en) | 1997-07-24 | 1997-07-24 | Pharmaceutical preparations containing dibenzo [b, e] oxepin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3828247B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005097104A1 (en) * | 2004-04-08 | 2005-10-20 | Kyowa Hakko Kogyo Co., Ltd. | SOLID PHARMACEUTICAL PREPARATION CONTAINING DIBENZ[b,e]OXEPINE DERIVATIVE |
| WO2010017885A2 (en) * | 2008-08-12 | 2010-02-18 | Merck Patent Gmbh | Use of 5-(7-methoxy-3,3-dimethyl-2,3-dihydro-1-benzoxepin-5-yl)-3-methyl- penta-2,4-dienoic acid as a cosmetic |
| JP2011020960A (en) * | 2009-07-16 | 2011-02-03 | Takada Seiyaku Kk | Solid olopatadine preparation and method for producing olopatadine tablet |
| KR101252863B1 (en) * | 2004-04-08 | 2013-04-09 | 교와 핫꼬 기린 가부시키가이샤 | Solid pharmaceutical preparation with improved stability and process for producing the same |
| CN110882223A (en) * | 2018-09-11 | 2020-03-17 | 海南中济医药科技有限公司 | Directly compressed olopatadine hydrochloride tablet formula |
-
1997
- 1997-07-24 JP JP19842797A patent/JP3828247B2/en not_active Expired - Lifetime
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005097104A1 (en) * | 2004-04-08 | 2005-10-20 | Kyowa Hakko Kogyo Co., Ltd. | SOLID PHARMACEUTICAL PREPARATION CONTAINING DIBENZ[b,e]OXEPINE DERIVATIVE |
| JPWO2005097104A1 (en) * | 2004-04-08 | 2007-08-16 | 協和醗酵工業株式会社 | Solid preparation containing dibenzo [b, e] oxepin derivative |
| JP2013047231A (en) * | 2004-04-08 | 2013-03-07 | Kyowa Hakko Kirin Co Ltd | SOLID PREPARATION CONTAINING DIBENZ[b,e]OXEPINE DERIVATIVE |
| KR101252863B1 (en) * | 2004-04-08 | 2013-04-09 | 교와 핫꼬 기린 가부시키가이샤 | Solid pharmaceutical preparation with improved stability and process for producing the same |
| JP5611502B2 (en) * | 2004-04-08 | 2014-10-22 | 協和発酵キリン株式会社 | Solid preparation containing dibenzo [b, e] oxepin derivative |
| JP2016029063A (en) * | 2004-04-08 | 2016-03-03 | 協和発酵キリン株式会社 | SOLID PREPARATION CONTAINING DIBENZ[b,e]OXEPINE DERIVATIVE |
| WO2010017885A2 (en) * | 2008-08-12 | 2010-02-18 | Merck Patent Gmbh | Use of 5-(7-methoxy-3,3-dimethyl-2,3-dihydro-1-benzoxepin-5-yl)-3-methyl- penta-2,4-dienoic acid as a cosmetic |
| WO2010017885A3 (en) * | 2008-08-12 | 2010-09-02 | Merck Patent Gmbh | Use of 5-(7-methoxy-3,3-dimethyl-2,3-dihydro-1-benzoxepin-5yl)-3-methyl- penta-2,4-dienoic |
| JP2011020960A (en) * | 2009-07-16 | 2011-02-03 | Takada Seiyaku Kk | Solid olopatadine preparation and method for producing olopatadine tablet |
| CN110882223A (en) * | 2018-09-11 | 2020-03-17 | 海南中济医药科技有限公司 | Directly compressed olopatadine hydrochloride tablet formula |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3828247B2 (en) | 2006-10-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5671560B2 (en) | Tetracycline metal complexes in solid dosage forms. | |
| KR101041203B1 (en) | Stable Imatinib Composition | |
| EP1513528B1 (en) | Pharmaceutical composition containing stabilised amorphous form of donepezil hydrochloride | |
| CA2535810A1 (en) | Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethylester or the salts thereof | |
| EP1309556A1 (en) | Amlodipine fumarate | |
| JP3828247B2 (en) | Pharmaceutical preparations containing dibenzo [b, e] oxepin derivatives | |
| KR100760448B1 (en) | Composition Containing Benzamidine Derivative and Method for Stabilizing Benzamidine Derivative | |
| EP1696881A2 (en) | Stable oral composition | |
| JPH1192369A (en) | Pharmaceutical preparation, its production and use of acidic additive for stabilization of cilansetron | |
| CA2455858A1 (en) | Pharmaceutical preparations containing aminobenzene- sulfonic acid derivatives as the active ingredient | |
| JP2005521751A (en) | Amlodipine nicotinate and method for producing the same | |
| EP0310999A1 (en) | Pharmaceutical composition for piperidinoalkanol derivatives | |
| JP2001233766A (en) | Pravastatin sodium tablet | |
| EP1880992A1 (en) | Stable modifications of tegaserod hydrogen maleate | |
| MXPA02000033A (en) | Polymorphs of crystalline (2-benzhydryl-1-azabicyclo[2,2, 2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-ammoniumchloride as nk-1 receptor antagonists. | |
| JPH0597801A (en) | Indole derivative and antiulcer agent comprising the same derivative as active ingredient | |
| EP2515860A1 (en) | Improved pharmaceutical compositions comprising cefdinir | |
| JP2003055217A (en) | Pharmaceutical composition | |
| HUT69719A (en) | Process for producing pharmaceutical preparations containing indole derivatives | |
| JP4473539B2 (en) | Pharmaceutical composition | |
| US5523289A (en) | Pharmaceutical composition | |
| JP2001354566A (en) | Tablet of nicergoline | |
| JP3573287B2 (en) | Super absorbent solid preparation | |
| JPH0818987B2 (en) | Oral cefalosporin composition | |
| AU2001100435A4 (en) | Amlodipine fumarate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20050608 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20050808 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20060110 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060309 |
|
| A911 | Transfer of reconsideration by examiner before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20060502 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20060607 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20060706 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090714 Year of fee payment: 3 |
|
| S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090714 Year of fee payment: 3 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090714 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100714 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110714 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110714 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120714 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130714 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140714 Year of fee payment: 8 |
|
| R154 | Certificate of patent or utility model (reissue) |
Free format text: JAPANESE INTERMEDIATE CODE: R154 |
|
| EXPY | Cancellation because of completion of term |