JP3503222B2 - Process for producing stabilized tablets of nicorandil - Google Patents
Process for producing stabilized tablets of nicorandilInfo
- Publication number
- JP3503222B2 JP3503222B2 JP29883894A JP29883894A JP3503222B2 JP 3503222 B2 JP3503222 B2 JP 3503222B2 JP 29883894 A JP29883894 A JP 29883894A JP 29883894 A JP29883894 A JP 29883894A JP 3503222 B2 JP3503222 B2 JP 3503222B2
- Authority
- JP
- Japan
- Prior art keywords
- nicorandil
- inositol
- weight
- tablets
- tablet
- 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.)
- Expired - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】Detailed Description of the Invention
【０００１】[0001]
【産業上の利用分野】本発明は、Ｎ−（２−ヒドロキシ
エチル）ニコチン酸アミド硝酸エステル（一般名ニコラ
ンジル）の安定化した錠剤の製造方法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing N- (2-hydroxyethyl) nicotinic acid amide nitrate (generic name nicorandil) stabilized tablets.
【０００２】[0002]
【従来の技術】ニコランジルは、冠血管拡張作用、冠動
脈攣縮抑制作用を有する一方、心血行動態や心機能に影
響を及ぼすことが少ないため、各種病型の狭心症に対す
る有効な治療薬として知られている。しかしニコランジ
ルは、結晶自体は比較的安定であるにもかかわらず、こ
れを錠剤の形態に圧縮成形すると、圧縮力の増加に伴っ
て不安定化し貯蔵中の含量低下が起こり易くなる。この
ため圧縮力に起因する錠剤中におけるニコランジルの不
安定化を防止するための検討が行われてきた。そのよう
な検討の結果として例えば、ステアリルアルコール、セ
タノール又はステアリン酸で被覆した後に打錠する方法
（特開昭57-145659 号）、及び、ステアリルアルコー
ル、ステアリン酸等の一層多い量と混合して常法により
錠剤とする方法（特開昭62-252723)が知られている。し
かし安定化に用いるこれらの高級脂肪アルコール及び高
級脂肪酸は、常温で脂ろう状且つ非水溶性である。錠剤
服用後のニコランジルの迅速な溶解という観点からは、
水溶性物質を用いた安定化が一層好ましいと考えられ
る。BACKGROUND OF THE INVENTION Nicorandil is known as an effective therapeutic drug for various types of angina pectoris because it has a coronary vasodilatory action and a coronary artery spasm inhibiting action, but has little effect on cardiac hemodynamics and cardiac function. Has been. However, although the crystal itself of nicorandil is relatively stable, when it is compression-molded into a tablet form, it becomes unstable with an increase in compression force, and the content tends to decrease during storage. Therefore, studies have been conducted to prevent destabilization of nicorandil in tablets due to the compression force. As a result of such studies, for example, a method of coating with stearyl alcohol, cetanol or stearic acid and then tableting (JP-A-57-145659), and mixing with stearyl alcohol, stearic acid or the like in a larger amount. A method of forming tablets by a conventional method (Japanese Patent Laid-Open No. 62-252723) is known. However, these higher fatty alcohols and higher fatty acids used for stabilization are waxy and water-insoluble at room temperature. From the viewpoint of rapid dissolution of nicorandil after taking tablets,
Stabilization with a water-soluble substance is considered to be more preferable.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、これら非水
溶性の高級脂肪アルコール、高級脂肪酸ではなく、水溶
性物質を用いて、打錠によるニコランジルの不安定化を
防止することを目的とする。SUMMARY OF THE INVENTION It is an object of the present invention to prevent destabilization of nicorandil by tableting by using a water-soluble substance instead of these water-insoluble higher fatty alcohols and higher fatty acids. .
【０００４】[0004]
【課題を解決するための手段】検討の結果本発明者は、
意外にもニコランジルをイノシトールと混合し、これ
を、錠剤の打錠に使用される慣用の賦形剤顆粒と混合し
て打錠したとき、イノシトールを用いない場合に比して
ニコランジルの安定性が著しく向上することを見い出し
た。更に、本発明者は、ニコランジルの錠剤においてイ
ノシトールに更にショ糖脂肪酸エステルを併用すると、
安定化効果が一層高まることをも見出した。加えて、本
発明は、イノシトール、又はイノシトール及びショ糖脂
肪酸エステルを配合することによる、安定なニコランジ
ル散剤をも見出した。As a result of the examination, the present inventor found that
Surprisingly, when nicorandil was mixed with inositol, and when this was mixed with conventional excipient granules used for tableting and tableted, the stability of nicorandil was better than that without inositol. It has been found that it is significantly improved. Further, the present inventor, when sucrose fatty acid ester is further used in combination with inositol in the tablet of nicorandil,
It was also found that the stabilizing effect is further enhanced. In addition, the present invention has also found a stable nicorandil powder by blending inositol or inositol and sucrose fatty acid ester.
【０００５】本発明は、ニコランジルをイノシトール、
又はイノシトール及びショ糖脂肪酸エステル、及び賦形
剤顆粒と混合して打錠することを特徴とする、安定なニ
コランジルの錠剤の製造方法である。The present invention uses nicorandil as inositol,
Alternatively, it is a method for producing a stable tablet of nicorandil, which comprises mixing with inositol and sucrose fatty acid ester and excipient granules to form tablets.
【０００６】本発明において使用するイノシトールの量
は、ニコランジル１重量部に対し好ましくは0.1 〜５重
量部、更に好ましくは0.5 〜２重量部、特に好ましくは
１〜1.2 重量部である。The amount of inositol used in the present invention is preferably 0.1 to 5 parts by weight, more preferably 0.5 to 2 parts by weight, and particularly preferably 1 to 1.2 parts by weight, relative to 1 part by weight of nicorandil.
【０００７】また、使用するショ糖脂肪酸エステルとし
ては、ＨＬＢ値が１〜５の範囲のものが好ましい。ショ
糖脂肪酸エステルを使用する場合には、イノシトール１
重量部に対するその使用量は、好ましくは２重量部以
下、より好ましくは0.1 〜0.5重量部、特に好ましくは
0.2 〜0.4 重量部である。The sucrose fatty acid ester used preferably has an HLB value in the range of 1-5. When using sucrose fatty acid ester, inositol 1
The amount used relative to parts by weight is preferably 2 parts by weight or less, more preferably 0.1 to 0.5 parts by weight, and particularly preferably
0.2 to 0.4 parts by weight.
【０００８】使用する賦形剤顆粒は、打錠により錠剤を
製造するために通常使用される賦形剤の顆粒であればよ
く、打錠による成形に適する限り組成について特に制限
はない。例えば、マンニトール、乳糖、コーンスター
チ、α化デンプン、結晶セルロース、カルボキシメチル
セルロースカルシウム、メチルセルロース、ヒドロキシ
プロピルセルロースその他を含むものであることができ
る。また、打錠による成形に適する限りニコランジルと
イノシトールとの混合物の量に対する賦形剤の量につい
ても特に制限はない。また同様の組成により、安定なニ
コランジル散剤が得られる。The excipient granules to be used may be granules of excipients usually used for producing tablets by tableting, and the composition is not particularly limited as long as it is suitable for molding by tableting. For example, it may contain mannitol, lactose, corn starch, pregelatinized starch, crystalline cellulose, carboxymethyl cellulose calcium, methyl cellulose, hydroxypropyl cellulose and the like. Further, the amount of the excipient relative to the amount of the mixture of nicorandil and inositol is not particularly limited as long as it is suitable for molding by tableting. Also, a similar composition gives a stable nicorandil powder.
【０００９】なお、ステアリン酸マグネシウムのような
滑沢剤その他の、錠剤の製造において通常用いられる補
助剤も、本発明において問題なく使用できる。Lubricants such as magnesium stearate and other adjuvants usually used in the production of tablets can be used in the present invention without any problem.
【００１０】本発明によれば、後述の安定性試験の部に
示したように、錠剤中におけるニコランジルの安定性が
著しく改善される。According to the present invention, the stability of nicorandil in tablets is remarkably improved, as shown in the stability test section below.
【００１１】[0011]
【実施例】以下実施例を挙げて本発明を更に説明する。
〔実施例１〕 錠剤
錠剤処方（１錠中）
ニコランジル 5 ｍｇ
イノシトール 6 ｍｇ
賦形剤顆粒*) 38.75 ｍｇステリン酸マグネシウム 0.25 ｍｇ
計 50.0 ｍｇ
(*； 賦形剤顆粒は、Ｄ−マンニトール382.5 ｇを30メ
ッシュ篩過し、α化デンプン0.25ｇを加えてよく混合し
た後、水を加えて練合し、これを造粒し乾燥して30メッ
シュ篩過し整粒することにより得た。以下の実施例、比
較例においても同様である。）
上記処方に従ってニコランジル結晶、イノシトール及び
賦形剤顆粒をよく混合し、30メッシュ篩過し、ステアリ
ン酸ン酸マグネシウムを加えて混合後、1.5 ｔ／ｃｍ2
の圧縮圧で打錠し、１錠の重量50ｍｇの製剤を得た。The present invention will be further described with reference to the following examples. [Example 1] Tablet tablet formulation (in 1 tablet) Nicorandil 5 mg Inositol 6 mg Excipient granule *) 38.75 mg Magnesium stearate 0.25 mg Total 50.0 mg (*; Excipient granule is 382.5 g D-mannitol) After sieving through 30 mesh, adding 0.25 g of pregelatinized starch and mixing well, water was added and kneaded, and this was granulated, dried and sieved through 30 mesh to obtain granules. The same applies to Examples and Comparative Examples.) According to the above formulation, nicorandil crystals, inositol and excipient granules are well mixed, sieved with 30 mesh, magnesium stearate is added and mixed, and then 1.5 t / cm 2
The tablets were compressed with a compression pressure of 1 to give a tablet with a weight of 50 mg.
【００１２】〔実施例２〕 錠剤
上記処方に従ってニコランジル、イノシトール、ショ糖
脂肪酸エステル及び賦形剤顆粒をよく混合し、30メッシ
ュ篩過し、ステアリン酸マグネシウムを加えて混合後、
1.5 ｔ／ｃｍ2 の圧縮圧で打錠し、１錠50ｍｇの製剤を
得た。Example 2 Tablet According to the above prescription, nicorandil, inositol, sucrose fatty acid ester and excipient granules are well mixed, sieved with 30 mesh, and after addition of magnesium stearate and mixing,
Tablets were compressed at a compression pressure of 1.5 t / cm 2 to give a preparation of 50 mg per tablet.
【００１３】〔比較例〕 錠剤
ニコランジル 5 ｍｇ
賦形剤顆粒 44.75 ｍｇステリン酸マグネシウム 0.25 ｍｇ
計 50.0 ｍｇ
上記処方に従ってニコランジル、賦形剤顆粒をよく混合
し、30メッシュ篩過し、ステアリン酸マグネシウムを加
えて混合後、1.5 ｔ／ｃｍ2 の圧縮圧で打錠し、１錠50
ｍｇの製剤を得た。Comparative Example Tablets Nicorandil 5 mg Excipient Granules 44.75 mg Magnesium Sterate 0.25 mg Total 50.0 mg According to the above prescription, nicorandil and excipient granules are thoroughly mixed, sieved with 30 mesh, and magnesium stearate is added. After mixing, press at a compression pressure of 1.5 t / cm 2 to make 1 tablet 50
mg formulation was obtained.
【００１４】〔安定性試験〕上記実施例１及び２並びに
比較例の各錠剤を、乾燥剤を入れたガラス瓶中に入れて
密栓し、60℃の過酷条件にて24時間、48時間及び72時間
保存し、下記の試験方法に従って測定し、ニコランジル
の安定性を比較した。
（試験方法）
１）試料溶液： 錠剤20以上を採り、その重量を精密に
測定し、粉末化して試料とした。試料約0.2 ｇを精密に
秤取し、これに移動相（アセトニトリル／水＝１：４）
を加えて超音波抽出し、移動相を加えて正確に100 ｍｌ
とした。この液をメンブランフィルター濾過し試料溶液
とした。 ２）標準溶液：
ニコランジル標準品20ｍｇを精密に秤取し、これを移
動相（アセトニトリル／水＝１：４）に溶かして正確に
100 ｍｌとし標準溶液とした。
３）測定： 試料溶液及び標準溶液の各10μｌにつき、
次の条件で液体クロマトグラフィーを行い、試料溶液の
ピーク面積Ａt1及び標準溶液のピーク面積Ａt2を求め
た。次いで、次の式によりニコランジルの含量（％）を
求めた。
ニコランジルの含量（％）＝ニコランジル標準品の量×
（Ａt1／Ａt2）×（錠剤平均重量[mg]／採取量[mg]）×
（１／表示重量）×100
液体クロマトグラフィーの操作条件は次の通りとした。
検出器： 紫外線吸光光度計（262 ｎｍ）
カラム： Inertcil ODS 6.0×150 ｍｍ
カラム温度： 40 ℃
移動相： アセトニトリル／水＝１：４
流量： 1.0 ｍｌ／分
注入量： 10μｌ[Stability Test] Each of the tablets of Examples 1 and 2 and Comparative Example above was placed in a glass bottle containing a desiccant and tightly stoppered, and under severe conditions of 60 ° C. for 24 hours, 48 hours and 72 hours. It preserve | saved and measured according to the following test method, and compared the stability of nicorandil. (Test method) 1) Sample solution: 20 tablets or more were taken, the weight thereof was precisely measured, and powdered to obtain a sample. Precisely weigh about 0.2 g of sample and put it in the mobile phase (acetonitrile / water = 1: 4).
And ultrasonically extract, add the mobile phase and add exactly 100 ml.
And This solution was filtered with a membrane filter to obtain a sample solution. 2) Standard solution:
Accurately weigh 20 mg of Nicorandil standard product and dissolve it in the mobile phase (acetonitrile / water = 1: 4).
100 ml was used as a standard solution. 3) Measurement: For each 10 μl of sample solution and standard solution,
Liquid chromatography was performed under the following conditions to determine the peak area At 1 of the sample solution and the peak area At 2 of the standard solution. Then, the content (%) of nicorandil was determined by the following formula. Nicorandil content (%) = Nicorandil standard amount x
(At 1 / At 2 ) × (average tablet weight [mg] / sample amount [mg]) ×
(1 / display weight) × 100 The operating conditions for liquid chromatography were as follows. Detector: Ultraviolet absorptiometer (262 nm) Column: Inertcil ODS 6.0 x 150 mm Column temperature: 40 ° C Mobile phase: Acetonitrile / water = 1: 4 Flow rate: 1.0 ml / min Injection volume: 10 μl
【００１５】（試験結果） 次の表に示す通り、実施例
１の錠剤においては、比較例の錠剤に比して安定性が著
しく向上した。また実施例２の錠剤においては、実施例
１の錠剤に比して安定性がなお一層向上した。(Test Results) As shown in the following table, the tablets of Example 1 had significantly improved stability as compared with the tablets of Comparative Example. The stability of the tablet of Example 2 was further improved as compared with the tablet of Example 1.
【００１６】[0016]
【表１】 [Table 1]
【００１７】〔実施例３〕 散剤
Ｄ−マンニトール500 ｇをα化デンプン3.25ｇ／250 ｍ
Ｌの水で流動層造粒した後、整流して造粒物を得た。こ
の造粒物の489 ｇにニコランジル５ｇ及びイノシトール
６ｇを混合し散剤を得た。Example 3 Powder D-mannitol (500 g) and pregelatinized starch (3.25 g / 250 m)
After fluidized bed granulation with L water, it was rectified to obtain a granulated product. 489 g of this granulated product was mixed with 5 g of nicorandil and 6 g of inositol to obtain a powder.
【００１８】〔実施例４〕 散剤
Ｄ−マンニトール500 ｇをα化デンプン3.25ｇ／250 ｍ
Ｌの水で流動層造粒した後、整流して造粒物を得た。こ
の造粒物の487 ｇにニコランジル５ｇ、イノシトール６
ｇ、及びショ糖脂肪酸エステル（ＨＬＢ＝１）２ｇを混
合し散剤を得た。Example 4 Powder D-mannitol (500 g) and pregelatinized starch (3.25 g / 250 m)
After fluidized bed granulation with L water, it was rectified to obtain a granulated product. To 487 g of this granulated product, 5 g of nicorandil and 6 of inositol
g and sucrose fatty acid ester (HLB = 1) 2 g were mixed to obtain a powder.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/00 ─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. 7 , DB name) A61K 31/00
Claims (4)
トール及びショ糖脂肪酸エステル、及び賦形剤顆粒と混
合して打錠することを特徴とする、安定化したニコラン
ジルの錠剤の製造方法。1. A method for producing a stabilized tablet of nicorandil, which comprises mixing nicorandil with inositol, or inositol and sucrose fatty acid ester, and excipient granules to form tablets.
0.1 〜５重量部を混合することを特徴とする、請求項１
の製造方法。2. Inositol to 1 part by weight of nicorandil
2. Mixing 0.1-5 parts by weight.
Manufacturing method.
0.1 〜５重量部及びショ糖脂肪酸エステル２重量部以下
を混合することを特徴とする、請求項１の製造方法。3. Inositol to 1 part by weight of nicorandil
The method according to claim 1, wherein 0.1 to 5 parts by weight and 2 parts by weight or less of the sucrose fatty acid ester are mixed.
デンプンを含んでなるものである、請求項１乃至３のい
ずれかに記載の製造方法。4. The method according to claim 1, wherein the excipient granules contain mannitol and α-gelatinized starch.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29883894A JP3503222B2 (en) | 1994-11-07 | 1994-11-07 | Process for producing stabilized tablets of nicorandil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29883894A JP3503222B2 (en) | 1994-11-07 | 1994-11-07 | Process for producing stabilized tablets of nicorandil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08133976A JPH08133976A (en) | 1996-05-28 |
| JP3503222B2 true JP3503222B2 (en) | 2004-03-02 |
Family
ID=17864880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29883894A Expired - Fee Related JP3503222B2 (en) | 1994-11-07 | 1994-11-07 | Process for producing stabilized tablets of nicorandil |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3503222B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2872705B1 (en) * | 2004-07-08 | 2008-07-18 | Aventis Pharma Sa | COMPOSITIONS CONTAINING NICORANDIL, PROCESS FOR PREPARATION AND USE |
| CN109406706A (en) * | 2018-11-29 | 2019-03-01 | 北京市药品检验所 | Method of the nicorandil tablet in relation to substance is measured using HPLC corrector factor method |
-
1994
- 1994-11-07 JP JP29883894A patent/JP3503222B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08133976A (en) | 1996-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4084309B2 (en) | Solid formulation containing a single crystal form | |
| US6531153B2 (en) | Composition with sustained release of levodopa and carbidopa | |
| US5006345A (en) | Direct tableting auxiliary | |
| US7943172B2 (en) | Film-coated tablet or granules containing as active ingredient a pyridylpyrimidine compound or a pharmaceutically acceptable salt of this compound | |
| CA1338553C (en) | Pharmaceutical granulate containing cellulose product | |
| EP1810676B1 (en) | Levetiracetam formulations and methods for their manufacture | |
| MXPA03008340A (en) | Atorvastatin calcium in a pharmaceutical form, composition thereof, and pharmaceutical formulation comprising atorvastatin calcium. | |
| JP6895779B2 (en) | Azilsartan-containing solid pharmaceutical composition | |
| JPH0768140B2 (en) | Stabilized medicinal substance, process for its preparation and stable medicinal preparation | |
| JP4709379B2 (en) | Pharmaceutical formulation containing levothyroxine sodium | |
| EP0365480A1 (en) | Dispersible formulation | |
| JP3110794B2 (en) | Preparation containing 1,4-dihydropyridine derivative | |
| CA2435714C (en) | Fenofibrate tablets | |
| JP2002520296A (en) | Drug levothyroxine preparation | |
| JPH10147524A (en) | Forskolin derivative-containing oral preparation and production of medicine preparation | |
| KR100624214B1 (en) | Pharmaceutical formulations | |
| JP2020169145A (en) | Pharmaceutical composition containing azilsartan | |
| JP3503222B2 (en) | Process for producing stabilized tablets of nicorandil | |
| JPH1192369A (en) | Pharmaceutical preparation, its production and use of acidic additive for stabilization of cilansetron | |
| JP3995414B2 (en) | Stable pharmaceutical composition | |
| KR100594606B1 (en) | Immediate release medicinal compositions for oral use | |
| WO2010027101A1 (en) | Solid preparation for medical use | |
| CA2118133C (en) | Aminoguanidine spray drying process | |
| JPH11349479A (en) | Stable enalapril maleate tablet | |
| JP4596586B2 (en) | Trehalose particles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20031125 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20031201 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |