JP2000026282A - Hard gelatin capsule agent having improved dissolution property - Google Patents
Hard gelatin capsule agent having improved dissolution propertyInfo
- Publication number
- JP2000026282A JP2000026282A JP10197887A JP19788798A JP2000026282A JP 2000026282 A JP2000026282 A JP 2000026282A JP 10197887 A JP10197887 A JP 10197887A JP 19788798 A JP19788798 A JP 19788798A JP 2000026282 A JP2000026282 A JP 2000026282A
- Authority
- JP
- Japan
- Prior art keywords
- weight
- capsule
- preparation according
- aminoacetic acid
- dissolution
- 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.)
- Pending
Links
Abstract
Description
【０００１】[0001]
【発明が属する技術分野】本発明は、主薬の溶出性が改
善された硬ゼラチンカプセル剤に関する。[0001] The present invention relates to a hard gelatin capsule having improved dissolution of a base drug.
【０００２】[0002]
【従来の技術】硬ゼラチンカプセル剤は、長期保存中等
に、カプセル剤皮であるゼラチン中のアミノ基が、充填
物中の還元糖やその他のアルデヒド類等とメイラード反
応等のアミノカルボニル反応をおこすことによって、ゼ
ラチンが分子内または分子間で架橋や重合等の経時変化
をおこして不溶化し、その結果、内包薬物の放出性が著
しく遅延する問題点がある。従来、このような問題を解
決する手段として、例えば特開昭４９−５９９８１７に
は、カプセル充填物中に各種の蛋白質類、アミノ酸類、
アミノ基含有の物質、または抗酸化剤等を配合する方法
が開示されており、アミノ酸類の一例としてアミノ酢酸
（グリシン）も記載されている。しかし、アミノ酢酸を
配合した硬ゼラチンカプセル剤の具体例は記載されてい
ない。また特開平８−９９８６９には、硬ゼラチンカプ
セル剤の不溶化を防止する手段として、カプセル充填物
中にフリーラジカル捕獲剤を配合する方法が開示されて
いる。この技術は、フリーラジカル捕獲剤によって、ア
ルデヒド類等の過酸化物の発生源となるフリーラジカル
の発生を防止するものであり、前記のアミノカルボニル
反応自体を直接抑制する手段ではない。またフリーラジ
カル捕獲剤の具体例として、アミノ酢酸は記載されてい
ない。2. Description of the Related Art In hard gelatin capsules, during long-term storage, amino groups in gelatin, which is the capsule skin, cause an aminocarbonyl reaction such as a Maillard reaction with reducing sugars and other aldehydes in the filler. As a result, gelatin undergoes a time-dependent change such as cross-linking or polymerization between molecules or between molecules, and becomes insoluble, and as a result, there is a problem that the release of the encapsulated drug is significantly delayed. Conventionally, as means for solving such a problem, for example, JP-A-49-599817 discloses various proteins, amino acids, and the like in a capsule filling.
A method of blending an amino group-containing substance or an antioxidant is disclosed, and aminoacetic acid (glycine) is also described as an example of amino acids. However, no specific examples of hard gelatin capsules containing aminoacetic acid are described. Japanese Patent Application Laid-Open No. 8-99869 discloses a method of blending a free radical scavenger in a capsule filling as a means for preventing insolubilization of a hard gelatin capsule. This technique prevents the generation of free radicals, which are sources of peroxides such as aldehydes, using a free radical scavenger, and is not a means for directly suppressing the aminocarbonyl reaction itself. Aminoacetic acid is not described as a specific example of the free radical scavenger.
【０００３】[0003]
【発明が解決しようとする課題】ゼラチンの不溶化が抑
制されて、主薬の溶出性が改善された新規な硬ゼラチン
カプセル剤の開発が要望されていた。There has been a demand for the development of a novel hard gelatin capsule in which the insolubilization of gelatin is suppressed and the dissolution of the active ingredient is improved.
【０００４】[0004]
【課題を解決するための手段】上記課題に鑑み本発明者
らは鋭意検討した結果、硬ゼラチンカプセル剤の充填物
中にアミノ酢酸を共存させれば、ゼラチンの不溶化が抑
制されて主薬の溶出性が改善されることを見出し、以下
に示す本発明を完成した。 （１）カプセル充填物中にアミノ酢酸を含有することを
特徴とする、溶出性が改善された硬ゼラチンカプセル剤
（以下、本カプセル剤ともいう）。 （２）カプセル剤皮に対してアミノ酢酸を０.５〜３０
重量％含有する、上記１記載の製剤。 （３）医薬活性成分として縮合イミダゾピリジン誘導体
を含有する、上記１または２記載の製剤。 （４）縮合イミダゾピリジン誘導体が、２−（イソオキ
サゾール−３−イル）−１,６,７,９−テトラヒドロイ
ミダゾ[４,５−ｄ]ピラノ[４,３−ｂ]ピリジン、その製
薬上許容される塩、またはそれらの水和物である、上記
３記載の製剤。 （５）カプセル剤皮に対してアミノ酢酸を１〜２０重量
％含有する、上記４記載の製剤。 （６）カプセル剤皮に対して崩壊剤を３０〜６０重量％
含有する、上記５載の製剤。 （７）カプセル剤皮に対して、２−（イソオキサゾール
−３−イル）−１,６,７,９−テトラヒドロイミダゾ
[４,５−ｄ]ピラノ[４,３−ｂ]ピリジン、その製薬上許
容される塩、またはそれらの水和物を１０〜５０重量
％、アミノ酢酸を１〜２０重量％、崩壊剤を３０〜６０
重量％含有する、上記４記載の製剤。 （８）４０℃／相対湿度７５％開放の条件下で３ケ月間
保存した場合の第１２改正日本薬局方に規定の溶出試験
法（第２法，パドル法）による２０分後の医薬活性成分
の溶出率が、６０％以上である、請求項４〜７のいずれ
かに記載の製剤。Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies. As a result, if aminoacetic acid is co-present in the filling of a hard gelatin capsule, the insolubilization of gelatin is suppressed and the elution of the main drug is prevented. The present inventors have found that the properties are improved, and have completed the present invention described below. (1) A hard gelatin capsule (hereinafter also referred to as the present capsule) having improved dissolution properties, characterized in that the capsule filler contains aminoacetic acid. (2) Aminoacetic acid is added to capsule skin from 0.5 to 30.
The preparation according to the above-mentioned 1, which contains 1% by weight. (3) The preparation according to the above (1) or (2), comprising a condensed imidazopyridine derivative as a pharmaceutically active ingredient. (4) the fused imidazopyridine derivative is 2- (isoxazol-3-yl) -1,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine; 4. The preparation according to the above 3, which is an acceptable salt or a hydrate thereof. (5) The preparation according to the above (4), which contains 1 to 20% by weight of aminoacetic acid based on the capsule skin. (6) 30-60% by weight of disintegrant based on capsule capsule skin
The formulation according to the above-mentioned 5, which contains. (7) To the capsule skin, 2- (isoxazol-3-yl) -1,6,7,9-tetrahydroimidazo
[4,5-d] pyrano [4,3-b] pyridine, a pharmaceutically acceptable salt thereof or a hydrate thereof is 10 to 50% by weight, aminoacetic acid is 1 to 20% by weight, and a disintegrant is 30-60
5. The preparation according to the above-mentioned 4, which contains by weight. (8) Pharmaceutical active ingredient after 20 minutes according to the dissolution test method (second method, paddle method) specified in the 12th revised Japanese Pharmacopoeia when stored for 3 months under the conditions of 40 ° C./75% relative humidity open The formulation according to any one of claims 4 to 7, wherein a dissolution rate of the product is 60% or more.
【０００５】（９）該溶出率が７０％以上である、上記
８記載の製剤。 （１０）該溶出率が８０％以上である、上記８記載の製
剤。 （１１）４０℃／相対湿度７５％開放の条件下で３ケ月
間保存した場合の第１２改正日本薬局方に規定の溶出試
験法（第２法，パドル法）による２０分後の医薬活性成
分の溶出率が、アミノ酢酸を含有しない対照製剤と比較
して２倍以上である、上記４〜７のいずれかに記載の製
剤。 （１２）上記１１に記載の溶出率を示す、上記７に記載
の製剤。 （１３）医薬活性成分としてベンゾチアゼピン誘導体を
含有する、上記１または２に記載の製剤。 （１４）ベンゾチアゼピン誘導体が、（２Ｓ−シス）−
３−アセトキシ−５−[３−（４−（２−メトキシフェ
ニル）−１−ピペラジニル）プロピル]−２，３−ジヒ
ドロ−２−（４−メトキシフェニル）−８−クロロ−
１，５−ベンゾチアゼピン−４（５Ｈ）−オン、その製
薬上許容される塩、またはそれらの水和物である、上記
１３記載の製剤。 （１５）カプセル剤皮に対してアミノ酢酸を１〜２０重
量％含有する、上記１４記載の製剤。(9) The preparation according to the above (8), wherein the dissolution rate is 70% or more. (10) The preparation according to the above item 8, wherein the dissolution rate is 80% or more. (11) Pharmaceutical active ingredient after 20 minutes according to the dissolution test method (second method, paddle method) specified in the 12th revised Japanese Pharmacopoeia when stored for 3 months under the conditions of 40 ° C./75% relative humidity open 8. The preparation according to any of 4 to 7 above, wherein the dissolution rate of the compound is at least twice as high as that of a control preparation containing no aminoacetic acid. (12) The preparation according to (7), which exhibits the dissolution rate according to (11). (13) The preparation according to the above (1) or (2), comprising a benzothiazepine derivative as a pharmaceutically active ingredient. (14) The benzothiazepine derivative is (2S-cis)-
3-acetoxy-5- [3- (4- (2-methoxyphenyl) -1-piperazinyl) propyl] -2,3-dihydro-2- (4-methoxyphenyl) -8-chloro-
14. The preparation according to the above 13, which is 1,5-benzothiazepine-4 (5H) -one, a pharmaceutically acceptable salt thereof, or a hydrate thereof. (15) The preparation according to the above (14), which comprises 1 to 20% by weight of aminoacetic acid based on the capsule skin.
【０００６】（１６）カプセル剤皮に対して崩壊剤を６
０〜９０重量％含有する、上記１５記載の製剤。 （１７）カプセル剤皮に対して、（２Ｓ−シス）−３−
アセトキシ−５−[３−（４−（２−メトキシフェニ
ル）−１−ピペラジニル）プロピル]−２，３−ジヒド
ロ−２−（４−メトキシフェニル）−８−クロロ−１，
５−ベンゾチアゼピン−４（５Ｈ）−オン、その製薬上
許容される塩、またはそれらの水和物を４０〜１２０重
量％、アミノ酢酸を１〜２０重量％、崩壊剤を６０〜９
０重量％含有する、上記１４記載の製剤。 （１８）４５℃／密栓の条件下で３ケ月間保存した場合
の、第１２改正日本薬局方に規定の溶出試験法（第２
法，パドル法）による２０分後の医薬活性成分の溶出率
が、６０％以上である、上記１４〜１７のいずれかに記
載の製剤。 （１９）該溶出率が７０％以上である、上記１８記載の
製剤。 （２０）該溶出率が８０％以上である、上記１８記載の
製剤。 （２１）４５℃／密栓の条件下で３ケ月間保存した場合
の、第１２改正日本薬局方に規定の溶出試験法（第２
法，パドル法）による２０分後の医薬活性成分の溶出率
が、アミノ酢酸を含有しない対照製剤と比較して1.５倍
以上である、上記１４〜１７のいずれかに記載の製剤。 （２２）上記２１に記載の溶出率を示す、上記１７記載
の製剤(16) Disintegrant 6
16. The preparation according to the above 15, which contains 0 to 90% by weight. (17) For capsule skin, (2S-cis) -3-
Acetoxy-5- [3- (4- (2-methoxyphenyl) -1-piperazinyl) propyl] -2,3-dihydro-2- (4-methoxyphenyl) -8-chloro-1,
40-120% by weight of 5-benzothiazepine-4 (5H) -one, a pharmaceutically acceptable salt thereof, or a hydrate thereof, 1-20% by weight of aminoacetic acid, and 60-9% of a disintegrant.
15. The preparation according to the above 14, comprising 0% by weight. (18) Dissolution test method prescribed in the 12th revised Japanese Pharmacopoeia when stored for 3 months under the condition of 45 ° C / sealed stopper (No. 2
The formulation according to any one of the above items 14 to 17, wherein a dissolution rate of the pharmaceutically active ingredient after 20 minutes by a paddle method is 60% or more. (19) The preparation according to the above (18), wherein the dissolution rate is 70% or more. (20) The preparation according to the above (18), wherein the dissolution rate is 80% or more. (21) Dissolution test method specified in the 12th revised Japanese Pharmacopoeia when stored for 3 months under the condition of 45 ° C / sealed stopper (No. 2
The pharmaceutical preparation according to any one of the above items 14 to 17, wherein a dissolution rate of the pharmaceutically active ingredient after 20 minutes by a paddle method) is 1.5 times or more as compared with a control preparation containing no aminoacetic acid. (22) The preparation according to the above 17, which exhibits the dissolution rate according to the above 21.
【０００７】本カプセル剤の主薬である医薬活性成分と
しては、特に限定されず、例えば種々の抗生物質、抗ウ
イルス薬、中枢神経薬（例：抗精神薬）、抹消神経薬、
循環器系疾患治療薬（例：降圧薬、心疾患治療薬）、抗
潰瘍薬、鎮痛薬等が例示される。中でも抗精神薬として
は、例えば特開平５−２８６９７３に記載の縮合イミダ
ゾピリジン誘導体等が例示され、とりわけ薬理活性等の
面から好ましい化合物は、その実施例２５に記載の２−
（イソオキサゾール−３−イル）−１,６,７,９−テト
ラヒドロイミダゾ[４,５−ｄ]ピラノ[４,３−ｂ]ピリジ
ン、その製薬上許容される塩、またはそれらの水和物
（以下、これらを総称して化合物１ともいう）である。
また循環器系疾患治療薬としては、例えば特開平５−２
０１８６５に記載のベンゾチアゼピン誘導体が例示さ
れ、とりわけ薬理活性等の面から好ましい化合物はその
実施例２０に記載の（２Ｓ−シス）−３−アセトキシ−
５−[３−（４−（２−メトキシフェニル）−１−ピペ
ラジニル）プロピル]−２，３−ジヒドロ−２−（４−
メトキシフェニル）−８−クロロ−１，５−ベンゾチア
ゼピン−４（５Ｈ）−オン、その製薬上許容される塩、
またはそれらの水和物（以下、これらを総称して化合物
２ともいう）である。これらの製薬上許容される塩とし
ては、無機塩基、アンモニア、有機塩基、無機酸、有機
酸、塩基性アミノ酸、ハロゲンイオン等により形成され
る塩又は分子内塩が例示される。該無機塩基としては、
アルカリ金属（Ｎａ，Ｋ等）、アルカリ土類金属（Ｃ
ａ，Ｍｇ等）、有機塩基としては、トリメチルアミン、
トリエチルアミン、コリン、プロカイン、エタノールア
ミン等が例示される。無機酸としては、塩酸、臭化水素
酸、硫酸、硝酸、リン酸等が例示される。有機酸として
は、ｐ―トルエンスルホン酸、メタンスルホン酸、ギ
酸、トリフルオロ酢酸、マレイン酸、クエン酸等が例示
される。塩基性アミノ酸としては、リジン、アルギン、
オルニチン、ヒスチジン等が例示される。The pharmaceutically active ingredient which is the main drug of the capsule is not particularly limited, and includes, for example, various antibiotics, antivirals, central nervous drugs (eg, antipsychotics), peripheral nerve drugs,
Cardiovascular disease drugs (eg, antihypertensive drugs, heart disease drugs), anti-ulcer drugs, analgesics and the like are exemplified. Above all, examples of the antipsychotics include condensed imidazopyridine derivatives described in JP-A-5-286973, and particularly preferable compounds from the viewpoint of pharmacological activity and the like are the compounds described in Example 25 thereof.
(Isoxazol-3-yl) -1,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine, a pharmaceutically acceptable salt thereof, or a hydrate thereof (Hereinafter, these are also collectively referred to as compound 1.)
Further, as a therapeutic agent for cardiovascular diseases, for example,
The benzothiazepine derivative described in No. 01865 is exemplified, and a particularly preferable compound from the viewpoint of pharmacological activity and the like is (2S-cis) -3-acetoxy- described in Example 20 thereof.
5- [3- (4- (2-methoxyphenyl) -1-piperazinyl) propyl] -2,3-dihydro-2- (4-
Methoxyphenyl) -8-chloro-1,5-benzothiazepin-4 (5H) -one, a pharmaceutically acceptable salt thereof,
Or hydrates thereof (hereinafter, these are also collectively referred to as compound 2). Examples of these pharmaceutically acceptable salts include salts formed by inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions, and the like, or internal salts. As the inorganic base,
Alkali metals (Na, K, etc.), alkaline earth metals (C
a, Mg, etc.), and as the organic base, trimethylamine,
Examples include triethylamine, choline, procaine, ethanolamine and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, citric acid and the like. As basic amino acids, lysine, algin,
Ornithine, histidine and the like are exemplified.
【０００８】医薬活性成分の配合量は、その種類、対象
疾患、患者の状態等に応じて、適宜設定すればよいが、
通常、カプセル剤全重量に対して約０.１〜４０重量
％、好ましくは約１〜３０重量％、さらに好ましくは約
５〜２０重量％である。カプセル全充填物に対しては、
約２〜５０重量％、好ましくは約３〜４０重量％、さら
に好ましくは約５〜３０重量％である。カプセル剤皮
（ゼラチン）に対しては、約５〜１５０重量％、好まし
くは約１０〜１００重量％、さらに好ましくは約２０〜
８５重量％である。アミノ酢酸の含有比は、カプセル剤
皮に対して約０.５〜３０重量％、好ましくは約１〜２
０重量％、さらに好ましくは約２〜１５重量％である。
含有比が低すぎるとカプセル剤皮の不溶化を充分に抑制
できず、また高すぎると嵩高となり、一カプセル当りの
主薬の含有比が低下したりあるいはカプセルサイズを大
きくせざるをえない等の弊害が生じるので、いずれにし
て好ましくない。本カプセル剤は、所望により、通常、
硬ゼラチンカプセル剤を調製する際に使用され得る慣用
の崩壊剤、賦形剤、結合剤、溶解助剤、静電除去剤、滑
沢剤、コーティング剤、光安定化剤等を含有し得る。[0008] The amount of the pharmaceutically active ingredient may be appropriately set according to the type, target disease, patient condition and the like.
Usually, it is about 0.1 to 40% by weight, preferably about 1 to 30% by weight, more preferably about 5 to 20% by weight, based on the total weight of the capsule. For the whole capsule filling,
It is about 2 to 50% by weight, preferably about 3 to 40% by weight, more preferably about 5 to 30% by weight. About 5 to 150% by weight, preferably about 10 to 100% by weight, and more preferably about 20 to 100% by weight based on the capsule skin (gelatin).
85% by weight. The content ratio of aminoacetic acid is about 0.5 to 30% by weight, preferably about 1 to 2% by weight, based on the capsule shell.
0% by weight, more preferably about 2 to 15% by weight.
If the content ratio is too low, the insolubilization of the capsule skin cannot be sufficiently suppressed, and if the content ratio is too high, it becomes bulky, and the adverse effects such as a decrease in the content ratio of the main drug per capsule or an increase in capsule size are required. Is not preferred in any case. The present capsule, if desired, is usually
It may contain conventional disintegrants, excipients, binders, dissolution aids, antistatic agents, lubricants, coating agents, light stabilizers and the like which can be used in preparing hard gelatin capsules.
【０００９】崩壊剤としては、例えば部分α化デンプ
ン、カルボキシメチルスターチナトリウム、カルボキシ
メチルセルロースカルシウム（ＣＭＣカルシウム）、低
置換度ヒドロキシプロピルセルロース（ＬＨＰＣ）、ク
ロスカルメロースナトリウム（例、Ac-Di-Sol，旭化成
（株））、ポリビニルポリピロリドン等が例示される
が、好ましくは、ＣＭＣカルシウム、ＬＨＰＣ等であ
る。崩壊剤の含量は、カプセル剤全体に対して通常、約
１〜６０重量％、好ましくは約３〜４０重量％、さらに
好ましくは約５〜２０重量％である。カプセル全充填物
に対しては、約２〜７０重量％、好ましくは約５〜５０
重量％、さらに好ましくは約１０〜３０重量％である。
カプセル剤皮に対しては、約１０〜１００重量％、好ま
しくは約２０〜９５重量％、さらに好ましくは約３０〜
９０重量％である。賦形剤としては、例えば乳糖、白
糖、Ｄ−マンニトール、コーンスターチ、バレイショデ
ンプン、ヒドロキシプロピルスターチ等が例示される
が、好ましくはＤ−マンニトール、コーンスターチ等あ
る。賦形剤の含量は、カプセル剤全体に対して通常、約
１０〜９０重量％、好ましくは約２０〜７０重量％、さ
らに好ましくは約３５〜６０重量％である。カプセル全
充填物に対して通常、約３０〜９５重量％、好ましくは
約４０〜８５重量％、さらに好ましくは約４５〜８０重
量％である。結合剤としては、例えばメチルセルロー
ス、ポリビニルピロリドン、ヒドロキシプロピルセルロ
ース（ＨＰＣ）、ポリビニルアルコール、ゼラチン、デ
キストリン等が例示されるが、好ましくはＨＰＣであ
る。結合剤の含量は、カプセル全充填物に対して、通
常、約０.５〜１０重量％、好ましくは約１〜５重量％
である。溶解助剤としては、例えばコハク酸が例示され
る。溶解助剤の含量は、カプセル全充填物に対して、通
常、約１〜５重量％である。静電除去剤としては、シリ
カ（例：カープレックス（シオノギ）、アエロジル（日
本アエロジル（株）））が例示される。静電除去剤の含
量は、カプセル全充填物に対して、通常、約0.１〜１重
量%である。[0009] Disintegrants include, for example, partially pregelatinized starch, sodium carboxymethyl starch, calcium carboxymethylcellulose (CMC calcium), low-substituted hydroxypropylcellulose (LHPC), croscarmellose sodium (eg, Ac-Di-Sol, Asahi Kasei Corporation, polyvinyl polypyrrolidone, etc. are exemplified, and preferably, CMC calcium, LHPC and the like. The content of the disintegrant is usually about 1 to 60% by weight, preferably about 3 to 40% by weight, more preferably about 5 to 20% by weight based on the whole capsule. About 2 to 70% by weight, preferably about 5 to 50% by weight, based on the total capsule filling.
%, More preferably about 10 to 30% by weight.
About 10 to 100% by weight, preferably about 20 to 95% by weight, more preferably about 30 to 100% by weight based on the capsule skin.
90% by weight. Examples of the excipient include lactose, sucrose, D-mannitol, corn starch, potato starch, hydroxypropyl starch and the like, and preferably include D-mannitol and corn starch. The content of the excipient is usually about 10 to 90% by weight, preferably about 20 to 70% by weight, more preferably about 35 to 60% by weight, based on the whole capsule. It is usually about 30-95% by weight, preferably about 40-85% by weight, more preferably about 45-80% by weight, based on the total capsule filling. Examples of the binder include methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose (HPC), polyvinyl alcohol, gelatin, dextrin and the like, with HPC being preferred. The content of the binder is usually about 0.5 to 10% by weight, preferably about 1 to 5% by weight, based on the whole capsule filling.
It is. Examples of the dissolution aid include succinic acid. The content of the dissolution aid is usually about 1 to 5% by weight based on the total filling of the capsule. Examples of the static removing agent include silica (eg, Carplex (Shionogi), Aerosil (Nippon Aerosil Co., Ltd.)). The content of the static removing agent is usually about 0.1 to 1% by weight based on the whole capsule filling.
【００１０】滑沢剤としては、ステアリン酸マグネシウ
ム、タルク、ショ糖脂肪酸エステルなどが例示される。
コーティング剤としては、ポリビニルアセタ−ルジエチ
ルアミノアセテ−ト、アクリル酸エチル・メタアクリル
酸メチル共重合体、アミノアルキルメタアクリレートコ
ポリマー、ヒドロキシプロピルメチルセルロースアセテ
ートサクシネート、ヒドロキシプロピルメチルセルロー
スフタレート、マクロゴール等が例示される。光安定化
剤としては、酸化チタン等が例示される。本カプセル剤
は、上記原料を用いて、混合、練合、製粒、乾燥、調
粒、滑混、カプセル充填等の操作を当該分野で周知の方
法に準じて行うことにより製造できる。カプセルとして
は、好ましくは日本薬局方に規定の３号または４号カプ
セルが使用される。Examples of the lubricant include magnesium stearate, talc, sucrose fatty acid ester and the like.
Examples of the coating agent include polyvinyl acetate diethylaminoacetate, ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, macrogol and the like. Is done. Examples of the light stabilizer include titanium oxide. The present capsule can be produced by using the above-mentioned raw materials and performing operations such as mixing, kneading, granulating, drying, granulating, lubricating, and filling capsules according to methods well known in the art. As the capsule, a No. 3 or No. 4 capsule prescribed in the Japanese Pharmacopoeia is preferably used.
【００１１】本カプセル剤における主薬溶出性の改善の
程度は、種々の溶出試験により実証され得るが、例えば
後記試験例に記載のごとく第１２改正日本薬局方等に規
定の溶出試験法によって示される。例えば主薬として前
記化合物１を含む本カプセル剤を、４０℃／相対湿度７
５％開放の条件下で３ケ月間保存した場合でも、該溶出
試験（条件：第２法（パドル法），５０ｒｐｍ，第２液
（ｐＨ約６.８））による試験開始後２０分後の化合物
１の溶出率を、好ましい態様として、カプセル内の主薬
含量に対して少なくとも６０％または７０％以上、特に
好ましくは８５〜９５％のレベルに維持できる。一方、
同条件下でアミノ酢酸を含有しない対照製剤を保存した
場合には、２０分後の化合物１の溶出率は４０％以下と
なり、保存当初の製剤と比べて大幅に低下する。すなわ
ち、化合物１は、本カプセル剤においてアミノ酢酸を配
合させることにより、例えば２０分後の溶出率を２倍以
上に改善できる。化合物１を含有する本カプセル剤の好
ましい態様としては、カプセル剤皮に対して、化合物１
を約１０〜５０重量％、アミノ酢酸を約１〜２０重量
％、崩壊剤を約３０〜６０重量％含有し、さらに好まし
くは化合物１を１５〜３５重量％、アミノ酢酸を３〜１
５重量％、崩壊剤を３５〜５５重量％含有し、特に好ま
しくは化合物１を２０〜３０重量％、アミノ酢酸を５〜
１０重量％、崩壊剤を４０〜５０重量％含有する。The degree of improvement in the dissolution of the active substance in the present capsule can be demonstrated by various dissolution tests. For example, as described in the test examples described below, it is shown by the dissolution test method prescribed in the Japanese Pharmacopoeia, twelfth revision. . For example, the present capsule containing the compound 1 as a main drug is treated at 40 ° C./relative humidity 7
Even when stored for 3 months under the condition of 5% release, 20 minutes after the start of the test using the dissolution test (conditions: second method (paddle method), 50 rpm, second solution (pH about 6.8)) In a preferred embodiment, the dissolution rate of Compound 1 can be maintained at a level of at least 60% or 70% or more, particularly preferably 85 to 95%, based on the active substance content in the capsule. on the other hand,
When the control preparation containing no aminoacetic acid was stored under the same conditions, the dissolution rate of Compound 1 after 20 minutes was 40% or less, which was significantly lower than the preparation at the time of storage. That is, Compound 1 can improve the dissolution rate after 20 minutes, for example, by a factor of two or more by incorporating aminoacetic acid in the present capsule. As a preferred embodiment of the present capsule containing compound 1, the compound 1
About 10 to 50% by weight, about 1 to 20% by weight of aminoacetic acid and about 30 to 60% by weight of a disintegrant, more preferably 15 to 35% by weight of compound 1, and 3 to 1% of aminoacetic acid.
5% by weight, 35 to 55% by weight of a disintegrant, particularly preferably 20 to 30% by weight of compound 1 and 5 to 5% of aminoacetic acid.
It contains 10% by weight and 40 to 50% by weight of a disintegrant.
【００１２】同様に前記化合物２を含む本カプセル剤
を、４５℃／密栓の条件下で３ケ月間保存した場合で
も、該溶出試験（条件：第２法（パドル法），５０ｒｐ
ｍ，ｐＨ４.０緩衝液）による２０分後の化合物２の溶
出率は、好ましい態様として、６０％または７０％以
上、特に好ましくは８０〜９０％のレベルに到達する。
一方、同条件下でアミノ酢酸を含有しない対照製剤を保
存した場合には、試験開始後２０分後の化合物２の溶出
率は約４５％となり、保存当初の製剤と比べて大幅に低
下する。すなわち、化合物２は、本カプセル剤におい
て、アミノ酢酸を配合させることにより、例えば２０分
後の溶出率を約１.５倍以上、好ましくは約１.８倍以上
に改善できる。化合物２を含有する本カプセル剤の好ま
しい態様としては、カプセル剤皮に対して、化合物２を
約６０〜１００重量％、アミノ酢酸を約１〜２０重量
％、崩壊剤を約６０〜９０重量％含有し、さらに好まし
くは化合物２を約７０〜９０重量％、アミノ酢酸を約１
〜１５重量％、崩壊剤を約６５〜８５重量％含有し、特
に好ましくは化合物２を約７５〜８５重量％、アミノ酢
酸を１〜１０重量％、崩壊剤を７０〜８０重量％含有す
る。Similarly, even when the present capsule containing Compound 2 is stored at 45 ° C./sealed stopper for 3 months, the dissolution test (conditions: the second method (paddle method), 50 rpm
m, pH 4.0 buffer) after 20 minutes the elution rate of compound 2 reaches, in a preferred embodiment, a level of at least 60% or 70%, particularly preferably 80-90%.
On the other hand, when the control preparation containing no aminoacetic acid was stored under the same conditions, the dissolution rate of Compound 2 after about 20 minutes from the start of the test was about 45%, which was significantly lower than the preparation at the time of storage. That is, Compound 2 can improve the dissolution rate after 20 minutes by, for example, about 1.5 times or more, preferably about 1.8 times or more, by adding aminoacetic acid to the present capsule. In a preferred embodiment of the present capsule containing compound 2, compound 2 is about 60 to 100% by weight, aminoacetic acid is about 1 to 20% by weight, and disintegrant is about 60 to 90% by weight based on the capsule skin. More preferably, about 70 to 90% by weight of compound 2 and about 1% of aminoacetic acid are contained.
-15% by weight, about 65-85% by weight of disintegrant, particularly preferably about 75-85% by weight of compound 2, 1-10% by weight of aminoacetic acid and 70-80% by weight of disintegrant.
【００１３】[0013]
【実施例】以下に本発明の実施例を示すが、これらは本
発明をなんら制限するものではない。試験化合物として
は以下のものを用いた。 化合物１：２−（イソオキサゾール−３−イル）−１,
６,７,９−テトラヒドロイミダゾ[４,５−ｄ]ピラノ
[４,３−ｂ]ピリジン・１リン酸・１水和物 化合物２：（２Ｓ−シス）−３−アセトキシ−５−[３
−（４−（２−メトキシフェニル）−１−ピペラジニ
ル）プロピル]−２，３−ジヒドロ−２−（４−メトキ
シフェニル）−８−クロロ−１，５−ベンゾチアゼピン
−４（５Ｈ）−オン・１クエン酸実施例１ （処方）化合物１、アミノ酢酸等を含むすべてのカプセ
ル内包成分を混合し、乾式粉末充填法によりカプセルに
充填した（以下、カプセルＡという）。その組成を表1
に示す。なお対照製剤として、アミノ酢酸を配合しない
他はカプセルＡ全く同じ組成のカプセルＢ（４号カプセ
ル、合計１６５.０ｍｇ）を調製した。EXAMPLES Examples of the present invention will be described below, but they do not limit the present invention. The following test compounds were used. Compound 1: 2- (isoxazol-3-yl) -1,
6,7,9-tetrahydroimidazo [4,5-d] pyrano
[4,3-b] pyridine • monophosphate • monohydrate Compound 2: (2S-cis) -3-acetoxy-5- [3
-(4- (2-methoxyphenyl) -1-piperazinyl) propyl] -2,3-dihydro-2- (4-methoxyphenyl) -8-chloro-1,5-benzothiazepine-4 (5H)- ON-1 citric acid Example 1 (Formulation) All capsule-containing components including compound 1, aminoacetic acid and the like were mixed and filled into a capsule by a dry powder filling method (hereinafter referred to as capsule A). Table 1 shows the composition
Shown in As a control preparation, Capsule B (No. 4 capsule, total 165.0 mg) having exactly the same composition as Capsule A except that aminoacetic acid was not added was prepared.
【００１４】[0014]
【表１】 （溶出試験）上記カプセルＡおよびＢについて、40℃、
RH(相対湿度)75%開放の条件下、3ヶ月保存したときの化
合物１の溶出曲線を、それぞれ図1および図２に示す。 試験条件：第１２改正日本薬局方溶出試験法 第２法
(パドル法) 回転数50rpm、第２液(pH約6.8，温度37℃) （結果）アミノ酢酸を添加しないカプセルＢでは、保存
初期に比べて３ケ月後の溶出率は著しく遅延し、１０分
後から徐々に溶出しだして例えば２０分後の溶出率は３
５％にとどまり、６０分後にようやく９０％が溶出し
た。一方、アミノ酢酸を添加したカプセルＡでは、５分
後には溶出しだして、２０分後には９１％の溶出率に達
した。すなわちアミノ酢酸の添加により、硬ゼラチンカ
プセル剤の不溶化が顕著に抑制されて、溶出率が改善さ
れることがわかった。[Table 1] (Dissolution test) For the capsules A and B, at 40 ° C,
The elution curves of Compound 1 when stored for 3 months under the condition of 75% RH (relative humidity) release are shown in FIGS. 1 and 2, respectively. Test conditions: 12th revision Japanese Pharmacopoeia dissolution test method 2
(Paddle method) Rotation speed 50 rpm, second liquid (pH about 6.8, temperature 37 ° C) (Result) In capsule B without addition of aminoacetic acid, the dissolution rate after 3 months was significantly delayed compared to the initial stage of storage, and 10 minutes Elution is gradually started later. For example, the elution rate after 20 minutes is 3
It remained at 5% and only 60% eluted after 60 minutes. On the other hand, in capsule A to which aminoacetic acid was added, elution started after 5 minutes, and reached 20% after 20 minutes. That is, it was found that the addition of aminoacetic acid markedly suppressed the insolubilization of the hard gelatin capsule and improved the dissolution rate.
【００１５】実施例２ （処方）化合物２、低置換度ヒドロキシプロピルセルロ
ース（LHPC31）、Ｄ−マンニトールおよびコハク酸を、
ヒドロキシプロピルセルロース（HPC SL）水溶液で湿式
造粒、乾燥、調粒した後、ステアリン酸マグネシウムを
滑混する時にアミノ酢酸も同時に混合してカプセルに充
填した（カプセルＣ）。その組成を表２に示す。なお対
照製剤として、アミノ酢酸を配合しない他は、カプセル
Ｃ全く同じ組成のカプセルＤ（３号カプセル、合計２３
０.０ｍｇ）を調製した。 Example 2 (Formulation) Compound 2, low-substituted hydroxypropylcellulose (LHPC31), D-mannitol and succinic acid were
After wet granulation, drying and granulation with an aqueous solution of hydroxypropylcellulose (HPC SL), aminoacetic acid was mixed at the same time as magnesium stearate was slid and filled into capsules (capsule C). The composition is shown in Table 2. As a control preparation, Capsule C having exactly the same composition as Capsule D (No. 3 capsules, total 23
0.0 mg).
【００１６】[0016]
【表２】 （溶出試験）上記カプセルＣおよびＤについて、45℃
密栓 の条件下、3ヶ月保存したときの化合物２の溶出
曲線を、それぞれ図３および図４に示す。 試験条件：第１２改正日本薬局方溶出試験法 第２法
(パドル法) 回転数50rpm、酢酸緩衝液(pH4.0、温度37
℃) （結果）アミノ酢酸を添加しないカプセルＤでは、保存
初期に比べて３ケ月後の溶出率は著しく遅延し、５分後
から徐々に溶出しだして例えば２０分後の溶出率は４３
％にとどまり、６０分後でも８０％には到達しなかっ
た。一方、アミノ酢酸を添加したカプセルＣでは、試験
開始後すぐに溶出しだして、２０分後にはすでに８４％
の溶出率に達した。すなわちアミノ酢酸の添加により、
硬ゼラチンカプセルの不溶化が顕著に抑制されて、溶出
率が改善されることがわかった。[Table 2] (Dissolution test) For the capsules C and D, 45 ° C
The elution curves of compound 2 when stored for 3 months under sealed conditions are shown in FIGS. 3 and 4, respectively. Test conditions: 12th revision Japanese Pharmacopoeia dissolution test method 2
(Paddle method) Rotation speed 50 rpm, acetate buffer (pH 4.0, temperature 37
(Results) In Capsule D to which aminoacetic acid was not added, the dissolution rate after 3 months was significantly delayed as compared to the initial stage of storage, and the dissolution rate gradually began after 5 minutes, for example, 43 minutes after 20 minutes.
% And did not reach 80% even after 60 minutes. On the other hand, in capsule C to which aminoacetic acid was added, dissolution began immediately after the start of the test, and after 20 minutes, 84%
Elution rate was reached. That is, by adding aminoacetic acid,
It was found that the insolubilization of the hard gelatin capsule was significantly suppressed and the dissolution rate was improved.
【００１７】[0017]
【発明の効果】本カプセル剤は、アミノ酢酸を含有して
いることによりカプセル剤皮の不溶化が抑制されてお
り、加温、加湿条件下で長期保存したとしてもカプセル
自体の経時変化が少なく、内包薬物の著しい溶出遅延は
認められない。また、アミノ酢酸は、タンパク質のよう
な高分子物質と比べてそれ自身が非常に安定でかつ水溶
性の高い物質であり、カプセルに内包させても製剤特性
への悪影響は懸念されない。According to the present invention, since the capsule contains aminoacetic acid, the insolubilization of the capsule skin is suppressed, and even if the capsule itself is stored for a long time under heating and humidification conditions, the capsule itself has little change with time. No remarkable elution delay of the encapsulated drug is observed. In addition, aminoacetic acid is a substance which is very stable and highly water-soluble in itself as compared with a polymer substance such as a protein, and there is no concern about adverse effects on the formulation properties even when encapsulated in a capsule.
【図１】アミノ酢酸を含有する化合物１の硬ゼラチンカ
プセル剤について、主薬の溶出性の経時変化を示すグラ
フである。BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a graph showing the change over time in the dissolution of the active ingredient of a hard gelatin capsule of Compound 1 containing aminoacetic acid.
【図２】アミノ酢酸を含有しない化合物１の硬ゼラチン
カプセル剤について、主薬の溶出性の経時変化を示すグ
ラフである。FIG. 2 is a graph showing the change over time in the dissolution of the active ingredient in a hard gelatin capsule of Compound 1 containing no aminoacetic acid.
【図３】アミノ酢酸を含有する化合物２の硬ゼラチンカ
プセル剤について、主薬の溶出性の経時変化を示すグラ
フである。FIG. 3 is a graph showing the time-dependent change in the dissolution of the active ingredient in a hard gelatin capsule of Compound 2 containing aminoacetic acid.
【図４】アミノ酢酸を含有しない化合物２の硬ゼラチン
カプセル剤について、主薬の溶出性の経時変化を示すグ
ラフである。FIG. 4 is a graph showing the change over time in the dissolution of the active ingredient of a hard gelatin capsule of Compound 2 containing no aminoacetic acid.
───────────────────────────────────────────────────── フロントページの続き Ｆターム(参考） 4C076 AA54 BB01 CC01 CC11 CC13 DD29 DD41C DD51B DD51L EE31B EE32B EE38A EE38B EE42H FF06 FF29 FF33 FF60 4C086 AA01 AA02 BC92 CB22 MA05 MA37 NA02 NA11 ZA18 ZA39 ZA40 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA54 BB01 CC01 CC11 CC13 DD29 DD41C DD51B DD51L EE31B EE32B EE38A EE38B EE42H FF06 FF29 FF33 FF60 4C086 AA01 AA02 BC92 CB22 MA05 MA37 NA02 ZA18 ZA18
Claims (22)
ことを特徴とする、溶出性が改善された硬ゼラチンカプ
セル剤。(1) A hard gelatin capsule having improved dissolution, characterized in that the capsule filler contains aminoacetic acid.
〜３０重量％含有する、請求項１記載の製剤。2. An aminoacetic acid of 0.5 to the capsule skin.
The preparation according to claim 1, which contains about 30% by weight.
誘導体を含有する、請求項１または２記載の製剤。3. The preparation according to claim 1, comprising a condensed imidazopyridine derivative as a pharmaceutically active ingredient.
ソオキサゾール−３−イル）−１,６,７,９−テトラヒ
ドロイミダゾ[４,５−ｄ]ピラノ[４,３−ｂ]ピリジン、
その製薬上許容される塩、またはそれらの水和物であ
る、請求項３記載の製剤。4. The fused imidazopyridine derivative is 2- (isoxazol-3-yl) -1,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine,
The formulation according to claim 3, which is a pharmaceutically acceptable salt thereof or a hydrate thereof.
０重量％含有する、請求項４記載の製剤。5. A capsule preparation containing 1 to 2 amino acetic acids.
The preparation according to claim 4, which contains 0% by weight.
重量％含有する、請求項５載の製剤。6. A disintegrant is added to the capsule skin in an amount of from 30 to 60.
The formulation according to claim 5, which contains about 10% by weight.
ゾール−３−イル）−１,６,７,９−テトラヒドロイミ
ダゾ[４,５−ｄ]ピラノ[４,３−ｂ]ピリジン、その製薬
上許容される塩、またはそれらの水和物を１０〜５０重
量％、アミノ酢酸を１〜２０重量％、崩壊剤を３０〜６
０重量％含有する、請求項４記載の製剤。7. Capsule skin is treated with 2- (isoxazol-3-yl) -1,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine, 10 to 50% by weight of a pharmaceutically acceptable salt or a hydrate thereof, 1 to 20% by weight of aminoacetic acid, 30 to 6% of a disintegrant.
The preparation according to claim 4, which contains 0% by weight.
ケ月間保存した場合の第１２改正日本薬局方に規定の溶
出試験法（第２法，パドル法）による２０分後の医薬活
性成分の溶出率が、６０％以上である、請求項４〜７の
いずれかに記載の製剤。8. Under conditions of 40 ° C./75% relative humidity open, 3
The dissolution rate of the pharmaceutically active ingredient after 20 minutes according to the dissolution test method (the second method, the paddle method) prescribed in the 12th revised Japanese Pharmacopoeia when stored for a period of six months is 60% or more. The preparation according to any one of the above.
載の製剤。9. The preparation according to claim 8, wherein said dissolution rate is 70% or more.
記載の製剤。10. The elution rate is 80% or more.
A formulation as described.
３ケ月間保存した場合の第１２改正日本薬局方に規定の
溶出試験法（第２法，パドル法）による２０分後の医薬
活性成分の溶出率が、アミノ酢酸を含有しない対照製剤
と比較して２倍以上である、請求項４〜７のいずれかに
記載の製剤。11. A drug after 20 minutes according to a dissolution test method (second method, paddle method) prescribed in the 12th revised Japanese Pharmacopoeia when stored for 3 months under the conditions of 40 ° C./75% relative humidity release. The preparation according to any one of claims 4 to 7, wherein the active ingredient dissolution rate is twice or more as compared with a control preparation containing no aminoacetic acid.
項７に記載の製剤。12. The preparation according to claim 7, which exhibits the dissolution rate according to claim 11.
導体を含有する、請求項１または２に記載の製剤。13. The preparation according to claim 1, comprising a benzothiazepine derivative as a pharmaceutically active ingredient.
ス）−３−アセトキシ−５−[３−（４−（２−メトキ
シフェニル）−１−ピペラジニル）プロピル]−２，３
−ジヒドロ−２−（４−メトキシフェニル）−８−クロ
ロ−１，５−ベンゾチアゼピン−４（５Ｈ）−オン、そ
の製薬上許容される塩、またはそれらの水和物である、
請求項１３記載の製剤。14. The benzothiazepine derivative is (2S-cis) -3-acetoxy-5- [3- (4- (2-methoxyphenyl) -1-piperazinyl) propyl] -2,3.
-Dihydro-2- (4-methoxyphenyl) -8-chloro-1,5-benzothiazepin-4 (5H) -one, a pharmaceutically acceptable salt thereof, or a hydrate thereof,
The preparation according to claim 13.
２０重量％含有する、請求項１４記載の製剤。15. An aminoacetic acid of 1 to capsule skin.
The preparation according to claim 14, which contains 20% by weight.
０重量％含有する、請求項１５記載の製剤。16. A disintegrant is added to the capsule shell in an amount of 60 to 9%.
The preparation according to claim 15, which contains 0% by weight.
−３−アセトキシ−５−[３−（４−（２−メトキシフ
ェニル）−１−ピペラジニル）プロピル]−２，３−ジ
ヒドロ−２−（４−メトキシフェニル）−８−クロロ−
１，５−ベンゾチアゼピン−４（５Ｈ）−オン、その製
薬上許容される塩、またはそれらの水和物を６０〜１０
０重量％、アミノ酢酸を１〜２０重量％、崩壊剤を６０
〜９０重量％含有する、請求項１４記載の製剤。17. With respect to capsule skin, (2S-cis)
-3-acetoxy-5- [3- (4- (2-methoxyphenyl) -1-piperazinyl) propyl] -2,3-dihydro-2- (4-methoxyphenyl) -8-chloro-
1,5-benzothiazepine-4 (5H) -one, a pharmaceutically acceptable salt thereof, or a hydrate thereof is used for 60 to 10
0% by weight, 1-20% by weight of aminoacetic acid, 60
The preparation according to claim 14, which contains about 90% by weight.
た場合の、第１２改正日本薬局方に規定の溶出試験法
（第２法，パドル法）による２０分後の医薬活性成分の
溶出率が、６０％以上である、請求項１４〜１７のいず
れかに記載の製剤。18. The storage of a pharmaceutically active ingredient after 20 minutes according to the dissolution test method (second method, paddle method) prescribed in the 12th revised Japanese Pharmacopoeia when stored at 45 ° C./sealed stopper for 3 months. The preparation according to any one of claims 14 to 17, wherein the dissolution rate is 60% or more.
８記載の製剤。19. The method according to claim 1, wherein the elution rate is 70% or more.
8. The preparation according to 8.
８記載の製剤。20. The method according to claim 1, wherein the elution rate is 80% or more.
8. The preparation according to 8.
た場合の、第１２改正日本薬局方に規定の溶出試験法
（第２法，パドル法）による２０分後の医薬活性成分の
溶出率が、アミノ酢酸を含有しない対照製剤と比較して
1.５倍以上である、請求項１４〜１７のいずれかに記載
の製剤。21. A method of dissolving a pharmaceutically active ingredient after 20 minutes according to a dissolution test method (second method, paddle method) prescribed in the 12th revised Japanese Pharmacopoeia when stored at 45 ° C./sealed stopper for 3 months. Dissolution rate is lower than that of the control product without aminoacetic acid.
The preparation according to any one of claims 14 to 17, which is 1.5 times or more.
項１７記載の製剤22. The preparation according to claim 17, which exhibits the dissolution rate according to claim 21.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10197887A JP2000026282A (en) | 1998-07-14 | 1998-07-14 | Hard gelatin capsule agent having improved dissolution property |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10197887A JP2000026282A (en) | 1998-07-14 | 1998-07-14 | Hard gelatin capsule agent having improved dissolution property |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2000026282A true JP2000026282A (en) | 2000-01-25 |
Family
ID=16381958
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10197887A Pending JP2000026282A (en) | 1998-07-14 | 1998-07-14 | Hard gelatin capsule agent having improved dissolution property |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2000026282A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003028723A1 (en) * | 2001-09-27 | 2003-04-10 | Saitama Daiichi Pharmaceutical Co., Ltd. | Pharmaceutical compositions for percutaneous absorption containing fused imidazopyridine derivatives |
| WO2004078173A1 (en) * | 2003-02-05 | 2004-09-16 | Shionogi & Co., Ltd. | Tablet having improved dissolution characteristics |
| JP2007516210A (en) * | 2003-07-15 | 2007-06-21 | ファイザー・インク | Stable pharmaceutical formulation |
| WO2011080647A2 (en) | 2009-12-28 | 2011-07-07 | Pfizer Inc. | Gelatin capsules and gelatin compositions for forming capsule coating |
| WO2012116021A1 (en) * | 2011-02-25 | 2012-08-30 | Milliken & Company | Capsules and compositions comprising the same |
| US8815916B2 (en) | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US9725684B2 (en) | 2011-02-25 | 2017-08-08 | Milliken & Company | Capsules and compositions comprising the same |
-
1998
- 1998-07-14 JP JP10197887A patent/JP2000026282A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003028723A1 (en) * | 2001-09-27 | 2003-04-10 | Saitama Daiichi Pharmaceutical Co., Ltd. | Pharmaceutical compositions for percutaneous absorption containing fused imidazopyridine derivatives |
| WO2004078173A1 (en) * | 2003-02-05 | 2004-09-16 | Shionogi & Co., Ltd. | Tablet having improved dissolution characteristics |
| JP2007516210A (en) * | 2003-07-15 | 2007-06-21 | ファイザー・インク | Stable pharmaceutical formulation |
| US8815916B2 (en) | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| WO2011080647A2 (en) | 2009-12-28 | 2011-07-07 | Pfizer Inc. | Gelatin capsules and gelatin compositions for forming capsule coating |
| WO2012116021A1 (en) * | 2011-02-25 | 2012-08-30 | Milliken & Company | Capsules and compositions comprising the same |
| WO2012116023A1 (en) * | 2011-02-25 | 2012-08-30 | Milliken & Company | Capsules and compositions comprising the same |
| JP2014512257A (en) * | 2011-02-25 | 2014-05-22 | ミリケン・アンド・カンパニー | Capsule and composition containing the same |
| US9725684B2 (en) | 2011-02-25 | 2017-08-08 | Milliken & Company | Capsules and compositions comprising the same |
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