JPH05213739A - Vitamin c injection solution - Google Patents
Vitamin c injection solutionInfo
- Publication number
- JPH05213739A JPH05213739A JP5704192A JP5704192A JPH05213739A JP H05213739 A JPH05213739 A JP H05213739A JP 5704192 A JP5704192 A JP 5704192A JP 5704192 A JP5704192 A JP 5704192A JP H05213739 A JPH05213739 A JP H05213739A
- Authority
- JP
- Japan
- Prior art keywords
- ascorbic acid
- vitamin
- injection
- active ingredient
- galactopyranosyl
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明はビタミンＣ注射剤に関す
るものであり、さらに詳しくは、６−Ｏ−β−Ｄ−ガラ
クトピラノシル−Ｌ−アスコルビン酸又はその塩を有効
成分とするビタミンＣ注射剤に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an injectable vitamin C, more specifically, vitamin C containing 6-O-β-D-galactopyranosyl-L-ascorbic acid or a salt thereof as an active ingredient. It relates to injections.
【０００２】[0002]
【従来の技術】ビタミンＣ（Ｌ−アスコルビン酸）は栄
養強化効果をはじめ、種々薬理作用を有する物質であ
り、種々の剤形の薬剤に配合されている。しかしなが
ら、アスコルビン酸は中性、塩基性の水溶液中では著し
く不安定であることから、注射剤に処方することは非常
に困難である。水溶液中での安定性を向上させるために
種々のＬ−アスコルビン酸誘導体が開発されている（特
開昭５７−１４０７８９号公報，特公昭５８−５９２０
号公報，特開昭６２−８４０７２号公報参照）。また、
特開平２−３１１４９０号公報には６−Ｏ−β−Ｄ−ガ
ラクトピラノシル−Ｌ−アスコルビン酸の報告がすでに
行われている。2. Description of the Related Art Vitamin C (L-ascorbic acid) is a substance having various pharmacological actions such as a nutrition-enhancing effect, and is incorporated into various dosage forms. However, ascorbic acid is extremely unstable in a neutral or basic aqueous solution, so that it is very difficult to formulate it into an injection. Various L-ascorbic acid derivatives have been developed in order to improve the stability in an aqueous solution (JP-A-57-140789 and JP-B-58-5920).
Japanese Patent Laid-Open No. 62-84072). Also,
Japanese Unexamined Patent Publication (Kokai) No. 2-311490 has already reported on 6-O-β-D-galactopyranosyl-L-ascorbic acid.
【０００３】[0003]
【発明が解決しようとする課題】６−Ｏ−β−Ｄ−ガラ
クトピラノシル−Ｌ−アスコルビン酸については特開平
２−３１１４９０号公報で医薬品分野への利用がすでに
述べられているが、ビタミンＣ注射剤としてはまだ使用
されていない。他のＬ−アスコルビン酸誘導体は注射剤
の有効成分としてはその安定性が依然不十分であり、安
定性が高くても生体内でＬ−アスコルビン酸活性を示さ
ないという問題があった。本発明は注射剤中において長
期間安定であり、かつ生体内において十分なＬ−アスコ
ルビン酸活性を示すビタミンＣ注射剤を提供することを
目的とするものである。The use of 6-O-β-D-galactopyranosyl-L-ascorbic acid in the pharmaceutical field has already been described in JP-A-2-31490. Not yet used as C injection. The stability of other L-ascorbic acid derivatives is still insufficient as an active ingredient of an injection, and there is a problem that even if the stability is high, L-ascorbic acid activity is not exhibited in vivo. An object of the present invention is to provide a vitamin C injection that is stable in an injection for a long period of time and exhibits sufficient L-ascorbic acid activity in vivo.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、このよう
な課題を解決するために鋭意検討の結果、Ｌ−アスコル
ビン酸誘導体として、６−Ｏ−β−Ｄ−ガラクトピラノ
シル−Ｌ−アスコルビン酸又はその塩が注射液中におい
て長期間安定であり、かつ生体内において十分なＬ−ア
スコルビン酸活性を示すことを見出し、本発明に到達し
た。すなわち、本発明は６−Ｏ−β−Ｄ−ガラクトピラ
ノシル−Ｌ−アスコルビン酸又はその塩を有効成分とし
てなることを特徴とするビタミンＣ注射剤を要旨とする
ものである。Means for Solving the Problems As a result of intensive studies to solve such problems, the present inventors have found that 6-O-β-D-galactopyranosyl-L as an L-ascorbic acid derivative. -The inventors have found that ascorbic acid or a salt thereof is stable in an injectable solution for a long period of time and exhibit a sufficient L-ascorbic acid activity in vivo, and thus arrived at the present invention. That is, the gist of the present invention is a vitamin C injection characterized by comprising 6-O-β-D-galactopyranosyl-L-ascorbic acid or a salt thereof as an active ingredient.
【０００５】以下、本発明を詳細に説明する。本発明に
用いるＬ−アスコルビン酸誘導体である６−Ｏ−β−Ｄ
−ガラクトピラノシル−Ｌ−アスコルビン酸は下記化学
式で示される構造を持ち、Ｌ−アスコルビン酸の６位の
ヒドロキシル基をガラクトシル化した構造を有する公知
の化合物であり、例えば、特開平２−３１１４９０号公
報に記載の方法に従って製造できる。すなわち、Ｌ−ア
スコルビン酸ナトリウムにβ−ガラクトシダ−ゼを触媒
としてラクト−スのガラクトシル基を転移させればよ
い。また、その精製は活性炭、陰イオン交換カラムなど
公知の方法を用いればよい。The present invention will be described in detail below. 6-O-β-D, which is an L-ascorbic acid derivative used in the present invention
-Galactopyranosyl-L-ascorbic acid is a known compound having a structure represented by the following chemical formula and having a structure in which the hydroxyl group at the 6-position of L-ascorbic acid is galactosylated. It can be manufactured according to the method described in the publication. That is, the galactosyl group of lactose may be transferred to sodium L-ascorbate using β-galactosidase as a catalyst. Further, the purification may be carried out by using a known method such as activated carbon or anion exchange column.
【０００６】[0006]
【化１】 [Chemical 1]
【０００７】６−Ｏ−β−Ｄ−ガラクトピラノシル−Ｌ
−アスコルビン酸は医薬品や食品に用いられる成分であ
るアスコルビン酸とガラクトースから構成されるＬ−ア
スコルビン酸誘導体であり、その毒性は極めて低く（ラ
ット経口投与によるＬＤ50＞１ｇ／Kg）、水溶液中での
安定性がアスコルビン酸に比べて著しく増大している。
さらに生体中ではＬ−アスコルビン酸とガラクトースに
加水分解され充分なビタミンＣ活性を示すことが明らか
となった。6-O-β-D-galactopyranosyl-L
-Ascorbic acid is an L-ascorbic acid derivative composed of ascorbic acid and galactose, which are components used in medicines and foods, and its toxicity is extremely low (LD50> 1g / Kg by oral administration to rats), The stability is significantly increased compared to ascorbic acid.
Further, it was revealed that in the living body, it was hydrolyzed into L-ascorbic acid and galactose and showed sufficient vitamin C activity.
【０００８】注射剤を調製する場合には、有効成分に安
定化剤等を加え、公知の方法により調製することができ
る。安定化剤としては、例えば、二酸化炭素、窒素、亜
硫酸水素ナトリウム、ピロ亜硫酸ナトリウム、アスコル
ビン酸、ブチルヒドロキシアニソ−ル、トコフェロ−
ル、ＥＤＴＡ等を用いることができる。In the case of preparing an injection, a stabilizer and the like may be added to the active ingredient to prepare an injection. Examples of the stabilizer include carbon dioxide, nitrogen, sodium hydrogen sulfite, sodium pyrosulfite, ascorbic acid, butylhydroxyanisole and tocopherol.
, EDTA, etc. can be used.
【０００９】このようにして調製したビタミンＣ注射剤
に配合する有効成分の含有量は、使用目的、症状、など
により異なるが０．０１〜１００重量％、好ましくは
０．０５〜８０重量％の範囲とする。また、その一日当
りの投与量は、使用目的、投与回数、剤形あるいは被投
与者の症状、年齢、体重などにより異なるが、通常、有
効成分が体重１Kg当り１〜５００mgの範囲が好ましく、
一日の投与量は５０〜５００mg／Kgの範囲が好ましい。The content of the active ingredient mixed in the vitamin C injection thus prepared varies depending on the purpose of use, symptoms, etc., but is 0.01 to 100% by weight, preferably 0.05 to 80% by weight. Range. The daily dose varies depending on the purpose of use, the number of administrations, the dosage form or symptoms of the recipient, age, body weight, etc., but usually the active ingredient is preferably in the range of 1 to 500 mg per 1 kg of body weight,
The daily dose is preferably in the range of 50 to 500 mg / Kg.
【００１０】すなわち、本発明によれば安定にビタミン
Ｃを配合し、かつ高いビタミンＣ活性を示すビタミンＣ
注射剤が得られる。That is, according to the present invention, vitamin C is blended stably with vitamin C and exhibits high vitamin C activity.
An injection is obtained.
【００１１】[0011]
【実施例】次に、本発明を参考例と実施例によって具体
的に説明する。 参考例１ ６−Ｏ−β−Ｄ−ガラクトピラノシル−Ｌ−アスコルビ
ン酸の製造 Ｌ−アスコルビン酸ナトリウム１．９ｇとガラクトース
一水和物１．５ｇを純水１０mlを加えて４０℃で攪はん
した。ｐＨを１Ｎ−塩酸で４〜５に調製した後、アスペ
ルギルス・オリーゼ（Aspergillus oryzae）由来のβガ
ラクトシダーゼ（シグマ社製グレ−ドXI）２０mgを加え
て攪はんし、４０℃で５時間放置した。煮沸して反応を
停止し、遠心分離（１万回転、２０分間）して上清を得
た。この上清を１００mlの活性炭カラムにアプライし、
純水２ｌで粗６−Ｏ−β−Ｄ−ガラクトシルアスコルビ
ン酸画分を得た。その溶出画分を１mlの陰イオン交換カ
ラム（Ｃｌ型）に付し、純水１００mlで糖分を除いた
後，０．０４Ｍの塩化ナトリウム液で６−Ｏ−β−Ｄ−
ガラクトシルアスコルビン酸を溶出した。溶出画分を濃
縮した後、陽イオン交換カラムで脱塩し、凍結乾燥し
た。その結果、１００mgの白色粉末の６−Ｏ−β−Ｄ−
ガラクトシル−Ｌ−アスコルビン酸を得た。EXAMPLES Next, the present invention will be specifically described with reference to examples and examples. Reference Example 1 Production of 6-O-β-D-galactopyranosyl-L-ascorbic acid 1.9 g of sodium L-ascorbate and 1.5 g of galactose monohydrate were added to 10 ml of pure water and stirred at 40 ° C. I spilled. After adjusting the pH to 4-5 with 1N-hydrochloric acid, 20 mg of β-galactosidase (Grade XI manufactured by Sigma) derived from Aspergillus oryzae was added and stirred, and the mixture was allowed to stand at 40 ° C for 5 hours. .. The reaction was stopped by boiling, and the supernatant was obtained by centrifugation (10,000 rotations, 20 minutes). This supernatant was applied to a 100 ml activated carbon column,
A crude 6-O-β-D-galactosyl ascorbic acid fraction was obtained with 2 liters of pure water. The elution fraction was applied to an anion exchange column (Cl type) of 1 ml, the sugar was removed with 100 ml of pure water, and then 6-O-β-D-was added with 0.04 M sodium chloride solution.
Galactosyl ascorbic acid was eluted. The eluate fraction was concentrated, desalted with a cation exchange column, and lyophilized. As a result, 100 mg of white powder of 6-O-β-D-
Galactosyl-L-ascorbic acid was obtained.
【００１２】実施例１ 以下の処方からなるビタミンＣ注射剤を常法に従い調製
した。 得られたビタミンＣ注射剤を４０℃にて１５日間保存
し、安定性試験を行った。すなわち、駐車剤中に残存す
るＬ−アスコルビン酸誘導体を高速液体クロマトグラフ
ィー（島津製作所製ＬＣ−２、カラム：バイオラッドＡ
ＭＩＮＥＸ ＨＰＸ−８７Ｈ、流速：０．６ｍｌ／分、
溶媒液：０．０１Ｍ Ｈ2 ＳＯ4 、検出波長：２４５ｎ
ｍ）にて定量した。その試験結果を表１に示した。な
お、表１中の数字は有効成分の残存率を示す。Example 1 A vitamin C injection having the following formulation was prepared according to a conventional method. The obtained vitamin C injection was stored at 40 ° C. for 15 days and a stability test was conducted. That is, the L-ascorbic acid derivative remaining in the parking agent was analyzed by high performance liquid chromatography (LC-2 manufactured by Shimadzu Corporation, column: Bio-Rad A).
MINEX HPX-87H, flow rate: 0.6 ml / min,
Solvent liquid: 0.01MH 2 SO 4 , Detection wavelength: 245n
m). The test results are shown in Table 1. The numbers in Table 1 show the residual ratio of the active ingredient.
【００１３】次に、実施例１で得られたビタミンＣ注射
剤の生体内ビタミンＣ活性試験を行った。すなわち、脱
脂粉乳、脱脂大豆にビタミンＣ以外の各種ビタミンを添
加した基礎飼料を用い、ハートレー系雄モルモット（体
重約２５０ｇ，１０尾）を２０日間飼育しながら、得ら
れたビタミンＣ注射剤（６−Ｏ−β−Ｄ−ガラクトピラ
ノシル−Ｌ−アスコルビン酸濃度：３４ｍｇ／ｍｌ）を
毎日０．０５ｍｌずつ腹腔内投与し、体重変化を測定し
た。対照群として注射用蒸留水を毎日０．０５ｍｌずつ
腹腔内投与した。その試験結果を表２に示した。なお、
表２中の数字はモルモットの平均体重の変化を示す。Next, the in vivo vitamin C activity test of the vitamin C injection obtained in Example 1 was conducted. That is, a vitamin C injectable solution (6 -O-β-D-galactopyranosyl-L-ascorbic acid concentration: 34 mg / ml) was intraperitoneally administered in an amount of 0.05 ml each day, and the change in body weight was measured. As a control group, 0.05 ml of distilled water for injection was intraperitoneally administered daily. The test results are shown in Table 2. In addition,
The numbers in Table 2 show changes in the average body weight of guinea pigs.
【００１４】さらに、上記試験のモルモットを、飼育開
始後１０日目に肝臓を摘出しその総ビタミンＣ含量を上
記安定性試験と同様に高速液体クロマトグラフィーで定
量しビタミンＣ代謝試験を行った。試験結果を表３に示
した。表３中の数字はモルモット臓器重量当りのビタミ
ンＣ量を示す。Furthermore, the guinea pigs of the above test were subjected to a vitamin C metabolism test by removing the liver 10 days after the start of breeding and quantifying the total vitamin C content by high performance liquid chromatography as in the above stability test. The test results are shown in Table 3. The numbers in Table 3 show the amount of vitamin C per guinea pig organ weight.
【００１５】比較例１ ６−Ｏ−β−Ｄ−ガラクトシルアスコルビン酸の代わり
に２−Ｏ−グルコシル−Ｌ−アスコルビン酸を使用する
他は実施例１と同様に行って注射剤を得、実施例１と同
様に安定性試験を行った。その安定性試験の結果を表１
に示した。Comparative Example 1 An injection was obtained in the same manner as in Example 1 except that 2-O-glucosyl-L-ascorbic acid was used instead of 6-O-β-D-galactosyl ascorbic acid. The stability test was conducted in the same manner as in 1. The result of the stability test is shown in Table 1.
It was shown to.
【００１６】比較例２ ６−Ｏ−β−Ｄ−ガラクトシルアスコルビン酸の代わり
に６−Ｏ−ステアリル−Ｌ−アスコルビン酸を使用する
他は実施例１と同様に行って注射剤を得、実施例１と同
様に安定性試験を行った。その安定性試験の結果を表１
に示した。Comparative Example 2 An injection was obtained in the same manner as in Example 1 except that 6-O-stearyl-L-ascorbic acid was used instead of 6-O-β-D-galactosyl ascorbic acid. The stability test was conducted in the same manner as in 1. The result of the stability test is shown in Table 1.
It was shown to.
【００１７】比較例３ ６−Ｏ−β−Ｄ−ガラクトシルアスコルビン酸の代わり
にＬ−アスコルビン酸を使用する他は実施例１と同様に
行って注射剤を得、実施例１と同様に安定性試験、生体
内ビタミンＣ活性試験、ビタミンＣ代謝試験を行った。
その安定性試験の結果を表１に、生体内ビタミンＣ活性
試験の結果を表２に、ビタミンＣ代謝試験の結果を表３
に示した。Comparative Example 3 An injection was obtained in the same manner as in Example 1 except that L-ascorbic acid was used instead of 6-O-β-D-galactosyl ascorbic acid, and stability was obtained in the same manner as in Example 1. The test, the in-vivo vitamin C activity test, and the vitamin C metabolism test were performed.
The stability test results are shown in Table 1, the in vivo vitamin C activity test results are shown in Table 2, and the vitamin C metabolism test results are shown in Table 3.
It was shown to.
【００１８】[0018]
【表１】 [Table 1]
【００１９】表１より明らかなごとく、Ｌ−アスコルビ
ン酸（比較例３）および６−Ｏ−β−Ｄ−ステアリル−
Ｌ−アスコルビン酸（比較例２）を有効成分として含む
注射剤は非常に不安定であり、経日と共に減少した。ま
た、２−Ｏ−グルコシル−Ｌ−アスコルビン酸（比較例
１）を有効成分として含む注射剤は比較的安定である
が、本発明の注射剤に比べて安定性はそれほど優れたも
のではなかった。これに対して本発明の６−Ｏ−β−Ｄ
−ガラクトピラノシル−Ｌ−アスコルビン酸（実施例
１）を有効成分として含む注射剤は１５日目においても
ほとんど減少しなくて、非常に安定であった。As is clear from Table 1, L-ascorbic acid (Comparative Example 3) and 6-O-β-D-stearyl-
The injection containing L-ascorbic acid (Comparative Example 2) as an active ingredient was very unstable and decreased with the passage of time. Further, the injection containing 2-O-glucosyl-L-ascorbic acid (Comparative Example 1) as an active ingredient is relatively stable, but the stability was not so excellent as compared with the injection of the present invention. .. On the other hand, 6-O-β-D of the present invention
The injection containing galactopyranosyl-L-ascorbic acid (Example 1) as an active ingredient was very stable with almost no decrease even on the 15th day.
【００２０】[0020]
【表２】 [Table 2]
【００２１】表２より明らかなごとく、対照群は、基礎
飼料は与えられるがビタミンＣが欠乏するため７日目以
降体重増加がほとんど見られず、１４日目以降に１０尾
中３尾が死亡した。これに対して本発明の６−Ｏ−β−
Ｄ−ガラクトピラノシル−Ｌ−アスコルビン酸（実施例
１）を有効成分として含む注射剤を投与した群は、Ｌ−
アスコルビン酸（比較例３）を有効成分として含む注射
剤を投与した群と同様に１日平均４〜５ｇの体重増加を
示し、投与期間中異常は認められなかった。すなわち、
本発明の６−Ｏ−β−Ｄ−ガラクトピラノシル−Ｌ−ア
スコルビン酸を有効成分として含む注射剤は生体内にお
いてＬ−アスコルビン酸と同様のビタミンＣ活性を示す
ものである。As is clear from Table 2, in the control group, since basic feed was given but vitamin C was deficient, almost no weight gain was observed after the 7th day, and 3 out of 10 fish died after the 14th day. did. On the other hand, 6-O-β- of the present invention
The group administered with the injection containing D-galactopyranosyl-L-ascorbic acid (Example 1) as an active ingredient was L-
Similarly to the group administered with the injection containing ascorbic acid (Comparative Example 3) as an active ingredient, the body weight gain was 4-5 g on average per day, and no abnormality was observed during the administration period. That is,
The injectable preparation of the present invention containing 6-O-β-D-galactopyranosyl-L-ascorbic acid as an active ingredient exhibits the same vitamin C activity as L-ascorbic acid in vivo.
【００２２】[0022]
【表３】 [Table 3]
【００２３】表３より明らかなごとく、対照群では飼料
中にＬ−アスコルビン酸が含まれていないため、肝臓中
にもビタミンＣはほとんど検出されなかった。本発明の
６−Ｏ−β−Ｄ−ガラクトピラノシル−Ｌ−アスコルビ
ン酸（実施例１）を有効成分として含む注射剤を投与し
た群は、Ｌ−アスコルビン酸（比較例３）を有効成分と
して含む注射剤を投与した群と同程度のビタミンＣ含量
を示した。この結果より、本発明の６−Ｏ−β−Ｄ−ガ
ラクトピラノシル−Ｌ−アスコルビン酸（実施例１）を
有効成分として含む注射剤を腹腔内投与することによ
り、その有効成分である６−Ｏ−β−Ｄ−ガラクトピラ
ノシル−Ｌ−アスコルビン酸が、ほぼ完全に加水分解さ
れてビタミンＣを生成することが示された。As is clear from Table 3, in the control group, since L-ascorbic acid was not contained in the diet, vitamin C was hardly detected in the liver. The group administered with the injection containing 6-O-β-D-galactopyranosyl-L-ascorbic acid (Example 1) of the present invention as an active ingredient contained L-ascorbic acid (Comparative Example 3) as an active ingredient. As a result, the vitamin C content was similar to that of the group administered with the injection. From these results, by injecting the injection containing 6-O-β-D-galactopyranosyl-L-ascorbic acid (Example 1) of the present invention as an active ingredient by intraperitoneal injection, the active ingredient is 6 It has been shown that -O-β-D-galactopyranosyl-L-ascorbic acid is almost completely hydrolyzed to produce vitamin C.
【００２４】[0024]
【発明の効果】本発明のビタミンＣ注射剤は、長期間安
定であり、かつ生体内において十分なＬ−アスコルビン
酸活性を有する。The vitamin C injection of the present invention is stable for a long period of time and has a sufficient L-ascorbic acid activity in vivo.
Claims (1)
Ｌ−アスコルビン酸又はその塩を有効成分としてなるこ
とを特徴とするビタミンＣ注射剤。1. 6-O-β-D-galactopyranosyl-
A vitamin C injection characterized by comprising L-ascorbic acid or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5704192A JPH05213739A (en) | 1992-02-07 | 1992-02-07 | Vitamin c injection solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5704192A JPH05213739A (en) | 1992-02-07 | 1992-02-07 | Vitamin c injection solution |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05213739A true JPH05213739A (en) | 1993-08-24 |
Family
ID=13044363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5704192A Pending JPH05213739A (en) | 1992-02-07 | 1992-02-07 | Vitamin c injection solution |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05213739A (en) |
-
1992
- 1992-02-07 JP JP5704192A patent/JPH05213739A/en active Pending
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