JPS60181052A - Stable isosorbide nitrate composition and its preparation - Google Patents
Stable isosorbide nitrate composition and its preparationInfo
- Publication number
- JPS60181052A JPS60181052A JP3618084A JP3618084A JPS60181052A JP S60181052 A JPS60181052 A JP S60181052A JP 3618084 A JP3618084 A JP 3618084A JP 3618084 A JP3618084 A JP 3618084A JP S60181052 A JPS60181052 A JP S60181052A
- Authority
- JP
- Japan
- Prior art keywords
- nitrate
- isosorbide nitrate
- composition
- insorbide
- solvent
- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は安定なインソルビド硝酸エステル製剤及びその
製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to stable insorbide nitrate formulations and methods for their production.
インソルビド硝酸エステルとしては、ジニトロエステル
体である硝酸イソンルビド及びモノニトロエステル体で
ある２−又は５−モノ硝酸インンルビドがあり、これら
はいずれも冠血管拡張作用を有することが知られている
。なかでも硝酸イソソルビドは狭心症発作の治療及び予
防を目的として、舌下錠、経口錠、徐放錠、注射剤等の
形で現在広く使用されている。Examples of insorbide nitrate include inrubido nitrate, which is a dinitro ester, and inrubido 2- or 5-mononitrate, which is a mononitro ester, and both of these are known to have a coronary vasodilatory effect. Among them, isosorbide nitrate is currently widely used in the form of sublingual tablets, oral tablets, sustained release tablets, injections, etc. for the purpose of treating and preventing angina attacks.
インソルビド硝酸エステルは、高温で気化し分解しやす
く、急速に加熱するか又は衝撃を与えると爆発するおそ
れがあるので、取扱いには十分な注意を要する。このも
のは弱いが刺激性の苦味を呈し、また揮散性を有するた
め製剤中から徐々に放出揮散して、製剤中の含有量を低
下する傾向が強く、ときには製剤表面での結晶組成が見
られる。Insorbide nitrate ester easily vaporizes and decomposes at high temperatures, and may explode if heated rapidly or subjected to impact, so sufficient care must be taken when handling it. This substance has a weak but irritating bitter taste, and because it is volatile, it tends to be gradually released and volatilized from the formulation, reducing the content in the formulation, and sometimes a crystalline composition can be seen on the surface of the formulation. .
本発明者らは、イノンルビド硝酸エステルのこれらの欠
点を改良するため種々検討した結果、イソソルビド硝酸
エステルに特定の成分を配合することにより、刺激性が
緩和されがっ揮散性が防止され、安定で取扱いも容易と
なり、錠剤、散剤、坐剤も固形製剤を調製する上で好適
であることを見出した。The present inventors conducted various studies to improve these drawbacks of ynone rubide nitrate, and found that by adding specific ingredients to isosorbide nitrate, irritation can be alleviated, volatility can be prevented, and stability can be achieved. It has been found that handling becomes easier, and tablets, powders, and suppositories are also suitable for preparing solid preparations.
本発明は、インソルビド硝酸エステルにポリビニルピロ
リドン、メチルセルロース、ヒドロキシプロピルセルロ
ース及びヒドロキシプロピルメチルセルロースよりなる
群から選ばれた１種又は２種以上の成分を配合してなる
インソルビド硝酸エステル組成物である。The present invention is an insorbide nitrate composition comprising insorbide nitrate ester and one or more components selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.
本発明の製剤は、好ましくはインンルビド硝酸エステル
１重量部及びポリビニルピロリドン、メチルセルロース
、ヒドロキシグロビルセルロース及ヒヒドロキシゾロビ
ルメチルセルロースよりなる群から選ばれた１種又は２
種以上の成分０．２〜６０重量部を、溶媒に溶解及び／
又は分散したのち溶媒を除去することにより製造される
。Preferably, the preparation of the present invention comprises 1 part by weight of innrubid nitrate and one or two selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxyglobilcellulose, and hydroxyzorobilmethylcellulose.
0.2 to 60 parts by weight of the above-specified components are dissolved in a solvent and/or
Alternatively, it can be manufactured by removing the solvent after dispersion.
本発明に用いられるポリビニルピロリドンとしては、日
本薬局方弁医薬品成分規格（１９８３）に収載のポリビ
ニルピロリドンに２５、ポリビニルピロリドンに３０、
ポリビニルピロリドンＫ ９０ カあげられる。メチル
セルローストシては、第十改正日本薬局方に収載のメチ
ルセルロースカ好マシい。ヒドロキシプロピルセルロー
スとしては、同薬局方収載のヒドロキシプロピルセルロ
ース、ヒドロキシプロピルメチルセルロースとしては、
同薬局方収載のヒドロキシプロピルメチルセルロース２
２０８、ヒドロキシプロピルメチルセルロース２９０６
．ヒドロキシプロピルメチルセルロース２９１ｏがあげ
られる。The polyvinylpyrrolidone used in the present invention is 25% polyvinylpyrrolidone, 30% polyvinylpyrrolidone listed in the Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients (1983),
Polyvinylpyrrolidone K 90. Methyl cellulose listed in the 10th revised Japanese Pharmacopoeia is better. As hydroxypropyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose listed in the same pharmacopoeia include:
Hydroxypropyl methylcellulose 2 listed in the same pharmacopoeia
208, hydroxypropyl methylcellulose 2906
．． Hydroxypropyl methylcellulose 291o is mentioned.
イソンルピド硝酸エステルと前記成分との配合割合は成
分の種類によって異なるが、イソンルビド硝酸エステル
１重量部に対し、前記の成分０．２〜６０重量部、特に
好ましくは１〜１５重量部の範囲が好適である。The blending ratio of isonrubide nitrate ester and the above-mentioned components varies depending on the type of the component, but it is preferably in the range of 0.2 to 60 parts by weight, particularly preferably 1 to 15 parts by weight, of the above-mentioned components per 1 part by weight of isonrubide nitrate. It is.
本発明の製剤を製造するに際しては、まずインソルビド
硝酸エステルを溶媒に溶解し、次いで前記の成分を溶解
及び／又は分散す呑＊キ藪溶媒としては例えばアセトン
、メタンニル、エタノール、インプロパツール、塩化メ
チレン、クロロホルム、水など並びにこれらの混合物が
用いられる。溶媒の使用量は、インソルビド硝酸エステ
ル１重量部に対し、２重量部以上好ましくはげ２０重量
部である。When producing the formulation of the present invention, first dissolve insorbide nitrate in a solvent, and then dissolve and/or disperse the above components. Examples of solvents include acetone, methanyl, ethanol, impropatol, Methylene, chloroform, water, etc. and mixtures thereof are used. The amount of the solvent used is 2 parts by weight or more, preferably 20 parts by weight, per 1 part by weight of insorbide nitrate.
次いでこの混合液に必要に応じ、矯味矯臭剤、着色剤、
増量剤、賦形剤などの添加剤を添加したのち溶媒を除去
する。Next, flavoring agents, coloring agents, and
After adding additives such as fillers and excipients, the solvent is removed.
溶媒の除去法としては工業的に通常実施されている方法
、すなわち常圧又は減圧下に加熱する方法、噴霧造粒す
る方法、得られた粉末な最終的に製剤とすることを考慮
してインソルビド硝酸エステルと前記の成分を含む溶液
を、目的の製剤とするために加える賦形剤に攪拌しなが
ら法論し、造粒したのち乾燥する方法、流動層造粒機に
賦形剤を入れ、混合溶液を噴霧し乾燥、造粒する方法な
どを用いることができる。The method for removing the solvent is one that is commonly used industrially, that is, heating under normal pressure or reduced pressure, spray granulation, and insorbide. A method in which a solution containing nitrate ester and the above ingredients is mixed with excipients added to make the desired formulation, granulated, and then dried; excipients are placed in a fluidized bed granulator and mixed. A method such as spraying a solution, drying, and granulating it can be used.
普通は、これらの成分は結合剤として用いられるが、主
薬と賦形剤等の医薬品添加物との混合粉末に、結合剤と
して溶媒に溶解したこれら成分を添加し、練合したのち
造粒する湿式造粒法によって得しれた薬剤に比べて、本
発明の薬剤は極めて優れた保存安定性を示した。Normally, these components are used as binders, but these components dissolved in a solvent are added as a binder to a mixed powder of the main drug and pharmaceutical additives such as excipients, kneaded, and then granulated. Compared to the drug obtained by wet granulation, the drug of the present invention showed extremely superior storage stability.
こうして得られたイソンルビド硝酸エステル組成物の粉
末あるいは粒剤は、そのままでも用いられるが、賦形剤
、崩壊剤、滑沢剤などの医薬品添加物を加え、常法によ
り顆粒剤、細粒剤、錠剤、バッカル剤、硬カプセル剤、
坐剤、軟膏剤等とすることができる。The powder or granules of the isonrubide nitrate ester composition obtained in this way can be used as is, but by adding pharmaceutical additives such as excipients, disintegrants, and lubricants, granules, fine granules, etc. Tablets, buccal preparations, hard capsules,
It can be made into suppositories, ointments, etc.
実施例１
５−モノ硝酸インンルビド２．５ｇをメタノール２０ｍ
１に溶解し、これにヒドロキシゾロピルメチルセルロー
ス２９１０の１２．５．９を加えて攪拌し、この混合液
を４５°Ｃで乾燥したのち、破砕して顆粒とする。Example 1 2.5 g of 5-mono-nitric acid innrubide was added to 20 m of methanol.
1, and 12.5.9 of Hydroxyzolopylmethylcellulose 2910 is added thereto and stirred. The mixture is dried at 45°C and then crushed to form granules.
実施例２
実施例１で得た混合液を乳糖２５．９及びばれいしょ殿
粉１０Ｉに注加し、練合したのち、２５メツシユのスク
リーンを通して造粒し、４５℃で乾燥して顆粒とする。Example 2 The mixed solution obtained in Example 1 was poured into 25.9 grams of lactose and 10 grams of potato starch, kneaded, and then granulated through a 25-mesh screen and dried at 45° C. to form granules.
実施例６
流動層造粒機を用い、５−モノ硝酸イソソルビド１０ｇ
をエタノール２００ ｍｌに溶解したのチ、ヒドロキシ
プロピルセルロース３０ｇを加えた混合液を乳糖１００
ｇに噴霧し、乾燥して顆粒とする。Example 6 Using a fluidized bed granulator, 10 g of isosorbide 5-mononitrate
was dissolved in 200 ml of ethanol, 30 g of hydroxypropyl cellulose was added, and the mixture was dissolved in 100 ml of lactose.
Spray onto g and dry to form granules.
実施例４
５−モノ硝酸イソソルビド２０．９をエタノール１０ｃ
Ｊｍｅに溶解し、これにメチルセルロース４０ｇを加え
た混合液を、乳糖８０ｇ、ばれいしょ殿粉４０，９及び
結晶セルロース２０ｇの混合粉末に注加して練合したの
ち、２５メツシユのスクリーンを通し、４５°Ｇで乾燥
して顆粒とする。Example 4 20.9 ml of isosorbide 5-mononitric acid was added to 10 c of ethanol.
A mixture obtained by dissolving Jme and adding 40 g of methylcellulose to it was poured into a mixed powder of 80 g of lactose, 40.9 g of potato starch, and 20 g of crystalline cellulose, kneaded, and passed through a 25-mesh screen. Dry at °G to form granules.
実施−例５
５−モノ硝酸イソソルビド２．５ｇをエタノール２０ｍ
１に溶解し、これにポリビニルピロリドンに３０の７．
５ ｇを加えて攪拌したのち２５メツシユのスクリーン
を通して造粒し、４５℃で乾燥して顆粒とする。Example 5 2.5 g of isosorbide 5-mononitrate was added to 20 m of ethanol.
1 and 30 parts of polyvinylpyrrolidone.
After adding 5 g and stirring, the mixture is granulated through a 25-mesh screen and dried at 45°C to form granules.
実施例６
硝酸イソソルビド２．５ｇをアセトン３０ｍ１に溶解り
、これにヒドロキシプロピルセルロース１２．５．９を
加えた混合液を、乳糖２５．９及びばれ〜・しよ殿粉１
０！ｑに注加して練合したのち、２５メツシユのスクリ
ーンを通して造粒し、４５℃で乾燥して顆粒とする。Example 6 A mixture of 2.5 g of isosorbide nitrate dissolved in 30 ml of acetone and 12.5.9 ml of hydroxypropyl cellulose was mixed with 25.9 ml of lactose and 1 ml of barley starch.
0! q and kneaded, then granulated through a 25-mesh screen and dried at 45°C to form granules.
実施例７
流動層造粒機を用い、硝酸イソンルぐド２．５１を塩化
メチレン−メタノール（重量比８：２）２００ｍ６に溶
解したのち、メチルセルロース１５ｇを加えた混合液を
乳糖１００ｇに噴霧し、乾燥して顆粒とする。Example 7 Using a fluidized bed granulator, 2.51 g of Isonerugde nitrate was dissolved in 200 m6 of methylene chloride-methanol (weight ratio 8:2), and then 15 g of methylcellulose was added, and the mixture was sprayed onto 100 g of lactose. Dry and make granules.
試験例
本発明の組成物を用い、インソルビド硝酸エステルの揮
散性、結晶生成及び刺激性について試験を行った。Test Example Using the composition of the present invention, tests were conducted on the volatility, crystal formation, and irritation of insorbide nitrate.
ａ）試料
実施例２及び乙により得られたインソルビド硝酸エステ
ル含有細粒剤及び下記表に示す成分のウチヒドロキシゾ
ロビルセルロースを除いた成分を混合し、これにエタノ
ールに溶解したヒドロキシゾロピルメチルセルロース溶
液を結合剤として加え、造粒したのち乾燥して得られた
細粒剤ｆＡ）を用いた。a) Mix the insorbide nitrate-containing fine granules obtained in Sample Example 2 and B and the components shown in the table below, excluding the hydroxyzorobyl cellulose, and add a hydroxyzolopyl methyl cellulose solution dissolved in ethanol. was added as a binder, granulated and dried to obtain a fine granule fA).
ｂ）実験法
シャーレに細粒剤を均一な厚さに入れ、４０°Ｃの恒温
器内に保存し、各試料の表面の変化を観察した。b) Experimental method The fine granules were placed in a petri dish to a uniform thickness and stored in a thermostat at 40°C, and changes in the surface of each sample were observed.
Ｃ）結果
各試料の表面での結晶生成の程度は下記表に示すとおり
で、本発明の組成物を用いた細粒剤は、表面での結晶生
成が明らかに減少し、口に含んだときの刺激性も緩和さ
れた。C) Results The degree of crystal formation on the surface of each sample is as shown in the table below, and the fine granules using the composition of the present invention clearly reduced crystal formation on the surface, and when put in the mouth. The irritation was also alleviated.
−二結晶生成なし 十：結晶生成あり 士：表面にわずかに変化あり 出願人 トーアエイヨー株式会社 代理人 弁理士 小 林 正 雄-No double crystal formation 10: Crystal formation Master: There are slight changes on the surface. Applicant: Toa Eiyo Co., Ltd. Agent: Patent Attorney Masao Kobayashi
Claims (1)
ドン、メチルセルロース、ヒドロキシプロピルセルロー
ス及びヒドロキシプロピルメチルセルロースよりなる群
から選ばれた１種又は２種以上の成分を配合することを
特徴とする、安定なインソルビド硝酸エステル組成物。 ２、 インソルビド硝酸エステル１重量部とポリビニル
ピロリドン、メチルセルロース、ヒドロキシプロピルセ
ルロース及びヒドロキシプロピルメチルセルロースより
なる群から選ばれた。１種又は２種以上の成分０．２〜
６０重量部とを、溶媒に溶解及び／又は分散したのち溶
媒を除去することを特徴とする、安定なイソン／レビド
硝酸エステル組成物の製造法。[Claims] 1. Stable, characterized by blending isosorbide nitrate with one or more components selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Insorbide nitrate composition. 2. 1 part by weight of insorbide nitrate ester and selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. One or more components 0.2~
A method for producing a stable isone/levido nitrate ester composition, which comprises dissolving and/or dispersing 60 parts by weight in a solvent and then removing the solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3618084A JPS60181052A (en) | 1984-02-29 | 1984-02-29 | Stable isosorbide nitrate composition and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3618084A JPS60181052A (en) | 1984-02-29 | 1984-02-29 | Stable isosorbide nitrate composition and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60181052A true JPS60181052A (en) | 1985-09-14 |
| JPH0244460B2 JPH0244460B2 (en) | 1990-10-04 |
Family
ID=12462533
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3618084A Granted JPS60181052A (en) | 1984-02-29 | 1984-02-29 | Stable isosorbide nitrate composition and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60181052A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0219161A2 (en) * | 1985-10-15 | 1987-04-22 | EURAND ITALIA S.p.A. | Process for the preparation of stabilized isosorbide-5-mononitrate tablets, being also of sustained release, and formulations thus obtained |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5593235A (en) * | 1979-01-05 | 1980-07-15 | Nec Corp | Integrated circuit |
-
1984
- 1984-02-29 JP JP3618084A patent/JPS60181052A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5593235A (en) * | 1979-01-05 | 1980-07-15 | Nec Corp | Integrated circuit |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0219161A2 (en) * | 1985-10-15 | 1987-04-22 | EURAND ITALIA S.p.A. | Process for the preparation of stabilized isosorbide-5-mononitrate tablets, being also of sustained release, and formulations thus obtained |
| JPS62123114A (en) * | 1985-10-15 | 1987-06-04 | ユーランド インターナショナル ソチエタ ペル アツィオニ | Stabilized isosorbide-5-mononitrate tablet and manufacture |
| JPH0524888B2 (en) * | 1985-10-15 | 1993-04-09 | Yuurando Spa |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0244460B2 (en) | 1990-10-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EXPY | Cancellation because of completion of term |