JPH07109254A - Stabilization of prostaglandin - Google Patents
Stabilization of prostaglandinInfo
- Publication number
- JPH07109254A JPH07109254A JP5251618A JP25161893A JPH07109254A JP H07109254 A JPH07109254 A JP H07109254A JP 5251618 A JP5251618 A JP 5251618A JP 25161893 A JP25161893 A JP 25161893A JP H07109254 A JPH07109254 A JP H07109254A
- Authority
- JP
- Japan
- Prior art keywords
- pge
- freeze
- dex
- dissolved
- prostaglandin
- 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]
【産業上の利用分野】本発明はプロスタグランジンＥ1
（以下ＰＧＥ1 と略称）凍結乾燥品の安定化法に関す
る。The present invention relates to a prostaglandin E 1
(Hereinafter abbreviated as PGE 1 ) A method for stabilizing a freeze-dried product.
【０００２】[0002]
【従来の技術】ＰＧＥ1 を含有する凍結乾燥品は医薬品
として有用である。しかしそれは熱安定性が悪く、長期
間（少なくとも２年間）にわたり保存するには冷蔵庫や
冷凍庫内で低温に保つ必要がある。そのような条件が必
要なく、室温で長期間（少なくとも２年間）保存しうる
凍結乾燥品を得ることが望まれている。2. Description of the Related Art A freeze-dried product containing PGE 1 is useful as a medicine. However, it has poor thermal stability and must be kept cold in the refrigerator or freezer for long-term storage (at least 2 years). It is desired to obtain a lyophilized product that does not require such conditions and can be stored at room temperature for a long time (at least 2 years).
【０００３】ＰＧＥ1 凍結乾燥品の熱安定性を改善する
ためには以下のような方法が知られている。 １）プロスタグランジン（以下ＰＧと略称）又はＰＧ類
似化合物をシクロデキストリンの（以下ＣＤと略称）包
接化合物にする方法。（特公昭５０−３３６２号又は特
公昭５２−３１４０４号）。The following methods are known to improve the thermal stability of PGE 1 freeze-dried products. 1) A method of converting a prostaglandin (hereinafter abbreviated as PG) or a PG-like compound into an inclusion compound of cyclodextrin (hereinafter abbreviated as CD). (Japanese Patent Publication No. 50-3362 or Japanese Patent Publication No. 52-31404).
【０００４】２）ＰＧＥ又はＰＧ類似化合物のＣＤ包接
化合物の水溶液にビタミンＣ又はクエン酸を加えて凍結
乾燥する方法。（特公昭５４−４３５７０号）。2) A method in which vitamin C or citric acid is added to an aqueous solution of a CD inclusion compound of PGE or a PG-like compound and freeze-dried. (Japanese Patent Publication No. 54-43570).
【０００５】３）ＰＧ又はＰＧ類似化合物のＣＤ、クエ
ン酸水溶液に少糖類又は分子量５０００以下の多糖類を
加えて凍結乾燥する方法。（特開昭５４−１０３８４４
号）。3) A method of freeze-drying by adding oligosaccharides or polysaccharides having a molecular weight of 5000 or less to an aqueous solution of PG or a PG-like compound and an aqueous citric acid solution. (JP-A-54-103844)
issue).
【０００６】４）ＰＧＥ及びＰＧＦ又はそれらの類似化
合物、及びＣＤ及び少糖類を凍結乾燥する方法。（特公
昭６１−５２１４６号）。4) A method of freeze-drying PGE and PGF or their similar compounds, and CD and oligosaccharides. (Japanese Patent Publication No. 61-52146).
【０００７】[0007]
【発明が解決しようとする課題】そこで我々は、注射可
能でありかつ室温で長期間（少なくとも２年間）保存可
能なＰＧＥ1 のあらたな凍結乾燥品を製造することを目
的として、研究を開始した。Therefore, we started a study for the purpose of producing a new lyophilized product of PGE 1 which is injectable and can be stored at room temperature for a long time (at least 2 years). .
【０００８】[0008]
【課題を解決するための手段】本発明者らはこの課題に
対処し鋭意研究を重ねた結果、ＰＧＥ1 及びα−ＣＤ水
溶液にデキストラン（以下ＤＥＸと略称）−４０を溶解
し凍結乾燥することにより、注射可能で室温下で高い安
定性を有する新たな組成物を見いだし本発明を完成し
た。Means for Solving the Problems As a result of addressing this problem and conducting extensive research, the present inventors have found that dextran (hereinafter abbreviated as DEX) -40 is dissolved in PGE 1 and α-CD aqueous solution and lyophilized. As a result, they have found a new composition that is injectable and has high stability at room temperature, and completed the present invention.
【０００９】ＤＥＸ−４０（協和醗酵ＫＫ）は、分子量
が４万のＤＥＸであり、意外にもα−ＣＤと併用するこ
とによりＰＧの凍結乾燥品の安定性を高めた。DEX-40 (Kyowa Fermentation KK) is a DEX having a molecular weight of 40,000, and surprisingly, the stability of the freeze-dried product of PG was improved by using it together with α-CD.
【００１０】ＰＧとしては、ＰＧＥ1 およびＰＧＥ2 が
あげられる。Examples of PG include PGE 1 and PGE 2 .
【００１１】本発明において使用される各成分の割合
は、ＰＧＥ1 １モルに対しα−ＣＤが２〜５０モルであ
り、好ましくは３〜１５モルである。ＤＥＸ−４０の量
はα−ＣＤの重量に対し１〜３００倍量であり、好まし
くは２〜１５０倍量である。The proportion of each component used in the present invention is 2 to 50 mol, preferably 3 to 15 mol of α-CD per 1 mol of PGE 1 . The amount of DEX-40 is 1 to 300 times, preferably 2 to 150 times the weight of α-CD.
【００１２】本発明組成物の製造はＰＧＥ1 のα−ＣＤ
包接化合物（ＰＧＥ1 ：α−ＣＤ＝３：９７）を水に溶
解した後、ＤＥＸ−４０またはその水溶液を加えて均一
に溶解し、得られた水溶液を凍結乾燥することによって
行われる。The preparation of the composition of the present invention is carried out by using α-CD of PGE 1.
The clathrate compound (PGE 1 : α-CD = 3: 97) is dissolved in water, DEX-40 or an aqueous solution thereof is added and uniformly dissolved, and the obtained aqueous solution is freeze-dried.
【００１３】以下に実施例により本発明を更に詳しく説
明するが、本発明はこれらに限定されるものではない。The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto.
【００１４】[0014]
［実施例１］ＰＧＥ1 ２０ｍｇ及びα−ＣＤ６８０ｍｇ
を注射用蒸留水約５００ｍｌに溶解する。そこへＤＥＸ
−４０を５０ｇまたは１００ｇを溶解し注射用蒸留水を
加えて全量を１０００ｍｌとする。常法に従って本水溶
液を無菌ろ過した後１ｍｌずつバイアルに分注する。凍
結乾燥後封栓しサンプルとした。対照として、実施例１
よりＤＥＸ−４０を除いてあとは同様にバイアルに分注
し、凍結乾燥後封栓し比較サンプルとした。[Example 1] PGE 1 20 mg and α-CD 680 mg
Is dissolved in about 500 ml of distilled water for injection. DEX there
Dissolve 50 g or 100 g of -40 and add distilled water for injection to make the total volume 1000 ml. After sterile filtration of this aqueous solution according to a conventional method, 1 ml is dispensed into each vial. After freeze-drying, the sample was sealed and used as a sample. As a control, Example 1
After removing DEX-40, the mixture was similarly dispensed into a vial, freeze-dried and sealed to obtain a comparative sample.
【００１５】これらのサンプルを５０゜Ｃで３０日間保
存し、残存するＰＧＥ1 を高速液体クロマトグラフ法で
測定した。即ち、凍結乾燥品を水に溶解し、本溶液に内
標準溶液を加え注入サンプルとした。本サンプルを逆層
系カラムを用いた高速液体クロマトグラフ（島津製作所
製、ＬＣ−１０ＡＤ）で分解物と分離し、ＵＶ検出器
（同、ＳＰＤ−１０Ａ）及びデ−タ処理装置（同Ｃ−Ｒ
７Ａ）を用い、常法によりＰＧＥ1 を定期的に分析し
た。結果を表１に示した。These samples were stored at 50 ° C. for 30 days, and the residual PGE 1 was measured by high performance liquid chromatography. That is, the freeze-dried product was dissolved in water, and the internal standard solution was added to this solution to prepare an injection sample. This sample was separated from decomposed products by a high performance liquid chromatograph (LC-10AD, manufactured by Shimadzu Corp.) using a reverse layer system column, and a UV detector (the same SPD-10A) and a data processor (the same C-). R
7A), PGE 1 was periodically analyzed by a conventional method. The results are shown in Table 1.
【００１６】[0016]
【表１】 ＤＥＸ−４０の添加効果が顕著に示された。[Table 1] The effect of adding DEX-40 was remarkably shown.
【００１７】［実施例２］ＰＧＥ1 ５００ｍｇ及びα−
ＣＤ１７ｇを注射用蒸留水約５００ｍｌに溶解する。そ
こへＤＥＸ−４０を５０ｇ又は１００ｇを溶解し、注射
用蒸留水を加えて乾燥後封栓し、サンプルとした。Example 2 500 mg of PGE 1 and α-
17 g of CD is dissolved in about 500 ml of distilled water for injection. 50 g or 100 g of DEX-40 was dissolved therein, distilled water for injection was added thereto, and the mixture was dried and sealed to obtain a sample.
【００１８】対照として、実施例２よりＤＥＸ−４０を
除いてあとは同様にバイアルに分注し、凍結乾燥後封栓
し、比較サンプルとした。これらのサンプルを５０゜Ｃ
で３０日間保存し、残存するＰＧＥ1 を実施例１と同様
に高速液体クロマトグラフ法で測定した。結果を表２に
示した。As a control, the same procedure as in Example 2 was repeated except that DEX-40 was omitted, and the mixture was similarly dispensed into a vial, freeze-dried, and sealed to obtain a comparative sample. These samples at 50 ° C
Was stored for 30 days, and the remaining PGE 1 was measured by the high performance liquid chromatography method as in Example 1. The results are shown in Table 2.
【００１９】[0019]
【表２】 ＤＥＸ−４０の添加効果が顕著に示された。[Table 2] The effect of adding DEX-40 was remarkably shown.
【００２０】[0020]
【発明の効果】本発明で見いだされた安定化剤ＤＥＸ−
４０を用いることによって熱安定性が良く、室温で長期
間（少なくとも２年間）保存可能なＰＧＥ1 含有凍結乾
燥注射製剤を製造できるようになった。The stabilizer DEX- found in the present invention
By using 40, it became possible to produce a lyophilized injectable preparation containing PGE 1 which has good thermal stability and can be stored at room temperature for a long time (at least 2 years).
Claims (1)
ストリン及びデキストラン４０を水に溶解し凍結乾燥す
ることを特徴とするプロスタグランジンＥ1 の安定化
法。 1. A method for stabilizing prostaglandin E 1 , which comprises dissolving prostaglandin E 1 , α-cyclodextrin and dextran 40 in water and freeze-drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5251618A JPH07109254A (en) | 1993-10-07 | 1993-10-07 | Stabilization of prostaglandin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5251618A JPH07109254A (en) | 1993-10-07 | 1993-10-07 | Stabilization of prostaglandin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07109254A true JPH07109254A (en) | 1995-04-25 |
Family
ID=17225510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5251618A Pending JPH07109254A (en) | 1993-10-07 | 1993-10-07 | Stabilization of prostaglandin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07109254A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005272458A (en) * | 2004-02-27 | 2005-10-06 | Ono Pharmaceut Co Ltd | Medical composition for oral administration |
| JP2005314413A (en) * | 2004-04-02 | 2005-11-10 | Ono Pharmaceut Co Ltd | Medicine composition for oral administration |
-
1993
- 1993-10-07 JP JP5251618A patent/JPH07109254A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005272458A (en) * | 2004-02-27 | 2005-10-06 | Ono Pharmaceut Co Ltd | Medical composition for oral administration |
| JP2005314413A (en) * | 2004-04-02 | 2005-11-10 | Ono Pharmaceut Co Ltd | Medicine composition for oral administration |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20020611 |