JP2007045788A - Method for preparing aqueous solution of glycyrrhizinic acid having high concentration - Google Patents
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Abstract
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本発明は、慢性肝疾患などの治療に有効なグリチルリチン酸又はその塩の高濃度水溶液およびその調製法に関する。 The present invention relates to a high-concentration aqueous solution of glycyrrhizic acid or a salt thereof effective for the treatment of chronic liver diseases and the like, and a method for preparing the same.
グリチルリチン酸モノアンモニウム塩は慢性肝疾患における肝機能異常の改善、湿疹・皮膚炎、蕁麻疹、皮膚掻痒症、薬疹・中毒疹、口内炎、小児ストロフルス、フリクテンに医療用医薬品として市販されている。慢性肝疾患の患者に対しては1日に４０〜１００ｍｇのグリチルリチン酸を必要とするが、その医薬品の水溶液中における濃度はグリチルリチン酸として２ｍｇ／ｍＬと低濃度である。高濃度溶液の調製を試みたとき、容易にゲルを形成し、注射剤として投与することができない。また経口投与など非注射剤として試みた場合、グリチルリチン酸はほとんど体内に吸収されない。 Glycyrrhizic acid monoammonium salt is marketed as a medical drug for improvement of liver function abnormality in chronic liver disease, eczema / dermatitis, urticaria, cutaneous pruritus, drug eruption / addiction eruption, stomatitis, pediatric stroflus, and frikuten. For patients with chronic liver disease, 40 to 100 mg of glycyrrhizic acid is required per day, but the concentration of the pharmaceutical in an aqueous solution is as low as 2 mg / mL as glycyrrhizic acid. When attempting to prepare a highly concentrated solution, it easily forms a gel and cannot be administered as an injection. Moreover, when it is tried as a non-injection agent such as oral administration, glycyrrhizic acid is hardly absorbed into the body.
グリチルリチン酸又はその塩の高濃度水溶液の調製法として、ポリエチレングリコールなどの高分子を用いる方法、エチルアルコールなどのアルコール類を添加する方法などが知られているが、安全性の面から問題である。
チョウジ油などの精油を１ｖ／ｖ％程度含有させた調製法（特許文献１）が報告されたが、少なくとも５時間以上の調製時間を要し、油成分を含有することで過剰の油を除去するために遠心分離機を用いた操作を必要とすること、また、たとえばチョウジ油成分の中には粘膜に有害とされるオイゲノールを含むことで安全性の面からまだ不十分であり、安全な処方とはいえない。
Although a preparation method (Patent Document 1) containing about 1 v / v% of essential oil such as clove oil has been reported, it takes at least 5 hours of preparation time, and excess oil is removed by containing oil components. In order to achieve this, it is necessary to operate with a centrifuge, and for example, clove oil component contains eugenol, which is harmful to mucous membranes. It is not a prescription.
もし生体に有害とされる物質を添加剤として一切使用せずにグリチルリチン酸又はその塩の高濃度水溶液を調製することができ、且つその高濃度水溶液が生理的条件であるｐＨ７．４付近、浸透圧比約１であれば、静脈内投与に変わる筋肉内あるいは皮下投与など投与ルートに多様性をもたらすことを可能とし、患者への苦痛などの負担を減らすことができる。また非注射剤の開発に対しても、添加物に有害な成分を全く含んでいない安全性の高い製剤として活用できる。 A highly concentrated aqueous solution of glycyrrhizic acid or a salt thereof can be prepared without using any substances that are harmful to the living body as additives, and the highly concentrated aqueous solution is in the vicinity of pH 7.4, which is a physiological condition. If the pressure ratio is about 1, it is possible to bring diversity to the administration route such as intramuscular or subcutaneous administration, which is changed to intravenous administration, and the burden on the patient can be reduced. In addition, it can be used as a highly safe formulation that does not contain any harmful ingredients in additives for the development of non-injectables.
この高濃度水溶液を調製するにあたり、乳化、振とう、撹拌、分離などの特殊な操作を必要としないことで１０〜３０分間という短時間で迅速に調製ができる。 In preparing this high-concentration aqueous solution, special operations such as emulsification, shaking, stirring, and separation are not required, so that it can be quickly prepared in a short time of 10 to 30 minutes.
本発明者らは、前記課題を解決するために研究を重ねた結果、グリチルリチン酸又はその塩の水溶液に少量のアルギニン又はヒスチジンを加えることにより、長期に亘って安定な低粘度且つ生理的条件を維持した高濃度のグリチルリチン酸又はその塩の水溶液が得られることを突き止めた。そしてさらに検討を重ね、本発明を完成した。
即ち、本発明は、
（１）アルギニン又はヒスチジンを含んでなるグリチルリチン酸又はその塩の高濃度水溶液、
（２）グリチルリチン酸塩がグリチルリチン酸モノアンモニウム塩である（１）記載のグリチルリチン酸又はその塩の高濃度水溶液、
（３）グリチルリチン酸塩又はその塩の濃度が５０ｍｇ／ｍＬ以上である（１）又は（２）のいずれかに記載のグリチルリチン酸又はその塩の高濃度水溶液、
（４）アルギニン又はヒスチジンは、Ｌ体、Ｄ体、ＤＬ体のいずれでもよく、また塩酸塩のように塩を形成するものも含む（１）〜（３）のいずれかに記載のグリチルリチン酸又はその塩の高濃度水溶液、
（５）水溶液のｐＨが５．５〜８．５の範囲内にある（１）〜（４）のいずれかに記載のグリチルリチン酸又はその塩の高濃度水溶液、
（６）グリチルリチン酸又はその塩の量が５０ｍｇ／ｍＬ以上であり、アルギニン又はヒスチジンの添加量が０．１〜５．０ｗ／ｖ％であり、加温が３０〜８０℃であるグリチルリチン酸又はその塩の高濃度水溶液の製造法、
である。
As a result of repeated researches to solve the above problems, the present inventors have added a small amount of arginine or histidine to an aqueous solution of glycyrrhizic acid or a salt thereof, so that a stable low viscosity and physiological condition can be obtained over a long period of time. It was found that an aqueous solution of the maintained high concentration glycyrrhizic acid or a salt thereof was obtained. And further examination was repeated and the present invention was completed.
That is, the present invention
(1) A highly concentrated aqueous solution of glycyrrhizic acid or a salt thereof comprising arginine or histidine,
(2) Glycyrrhizic acid or a high concentration aqueous solution of the salt thereof according to (1), wherein the glycyrrhizinate is monoammonium glycyrrhizinate,
(3) The high concentration aqueous solution of glycyrrhizic acid or a salt thereof according to any one of (1) or (2), wherein the concentration of glycyrrhizinate or a salt thereof is 50 mg / mL or more,
(4) Arginine or histidine may be any of L-form, D-form, and DL-form, and includes glycyrrhizic acid according to any one of (1) to (3) including those that form a salt such as hydrochloride. A highly concentrated aqueous solution of the salt,
(5) A highly concentrated aqueous solution of glycyrrhizic acid or a salt thereof according to any one of (1) to (4), wherein the pH of the aqueous solution is in the range of 5.5 to 8.5,
(6) The amount of glycyrrhizic acid or a salt thereof is 50 mg / mL or more, the addition amount of arginine or histidine is 0.1 to 5.0 w / v%, and the heating is 30 to 80 ° C. A method for producing a highly concentrated aqueous solution of the salt,
It is.
本発明のグリチルリチン酸又はその塩の高濃度水溶液は、たとえば冷蔵保存において白濁又はゲルを形成することなく、長期間の保存において安定した状態を維持できる。したがって、例えば１００ｍｇ／ｍＬのグリチルリチン酸水溶液を調製することによって、慢性肝疾患患者に対して静脈内への点滴投与ではなく、筋肉内あるいは皮下などに少量投与することで同等の効果を得ることができる。 The high-concentration aqueous solution of glycyrrhizic acid or a salt thereof of the present invention can maintain a stable state during long-term storage without forming cloudiness or gel in refrigerated storage, for example. Therefore, for example, by preparing a 100 mg / mL aqueous solution of glycyrrhizic acid, it is possible to obtain the same effect by administering a small amount intramuscularly or subcutaneously to a patient with chronic liver disease instead of intravenous infusion. it can.
アルギニン又はヒスチジンは、アミノ酸である。これらのＬ体は生体成分であり、アミノ酸製剤などの医薬品として、又は食品として利用されている。Ｌ−アルギニンは安定化剤、緩衝剤などの製剤添加物としても用いられ、製剤添加物としての最大使用量は、医薬品添加物辞典２０００（薬事日報社）の記載において、静脈内注射で４５７．５ｍｇとされている。Ｌ−ヒスチジンは安定化剤として製剤添加物にも用いられ、製剤添加物としての最大使用量は、医薬品添加物辞典２０００（薬事日報社）の記載において、静脈内注射で６２４ｍｇとされている。本発明の高濃度水溶液中のグリチルリチン酸の濃度を１００ｍｇ／ｍＬ、アミノ酸の濃度を５．０ｗ／ｖ％として調製したとき、慢性肝疾患の患者にグリチルリチン酸として１日に２００ｍｇを投与する場合、これらアミノ酸の含量はわずか１００ｍｇとなる。したがって、添加したアミノ酸が大量に体内に投与されることはない。 Arginine or histidine is an amino acid. These L-forms are biological components and are used as pharmaceuticals such as amino acid preparations or as foods. L-arginine is also used as a pharmaceutical additive such as a stabilizer and a buffer. The maximum amount of the pharmaceutical additive used is 457.75 by intravenous injection as described in the Pharmaceutical Additives Dictionary 2000 (Pharmaceutical Daily). 5 mg. L-histidine is also used as a stabilizer in pharmaceutical additives, and the maximum amount used as a pharmaceutical additive is 624 mg by intravenous injection as described in Pharmaceutical Additives Dictionary 2000 (Pharmaceutical Daily). When the concentration of glycyrrhizic acid in the high-concentration aqueous solution of the present invention is adjusted to 100 mg / mL and the amino acid concentration is set to 5.0 w / v%, 200 mg per day as glycyrrhizic acid is administered to a patient with chronic liver disease. The content of these amino acids is only 100 mg. Therefore, a large amount of added amino acid is not administered into the body.
本発明のグリチルリチン酸又はその塩の高濃度水溶液は、０．１〜５．０ｗ／ｖ％好ましくは１．０〜４．５ｗ／ｖ％になるようにアルギニン又はヒスチジンを添加し、３０〜１００ｍＭのリン酸塩緩衝液を加えて、３０〜８０℃、好ましくは４０〜６０℃に加温して溶解し、室温に戻す。 Arginine or histidine is added so that the high concentration aqueous solution of glycyrrhizic acid or a salt thereof of the present invention is 0.1 to 5.0 w / v%, preferably 1.0 to 4.5 w / v%, and 30 to 100 mM. The phosphate buffer solution is added, dissolved at 30 to 80 ° C., preferably 40 to 60 ° C., and returned to room temperature.
ｐＨ調整剤は加えなくても差し支えないが、生理的条件であるｐＨ７．４に近づけるために局方アンモニア水などの適当な溶液を加えてもよい。 A pH adjusting agent may not be added, but an appropriate solution such as pharmacological ammonia water may be added in order to approach the physiological condition of pH 7.4.
（１）実施例１で用いた機器は、次の通りである。
恒温槽（ＤＳ−６１、ヤマト）
恒温水浴（ＤＸ−１０、タイテック）
冷却器（８０ＬＦ、タイテック）
ｐＨメーター（Ｄ−１４、堀場）
浸透圧計（ＯＭ−８０２Ｄ、ＶＯＧＥＬ）
高速液体クロマトグラフィー（６５５、日立）
(1) The equipment used in Example 1 is as follows.
Constant temperature bath (DS-61, Yamato)
Constant temperature water bath (DX-10, Tytec)
Cooler (80LF, Taitec)
pH meter (D-14, Horiba)
Osmometer (OM-802D, VOGEL)
High performance liquid chromatography (655, Hitachi)
（２）リン酸塩緩衝液の調製
リン酸水素二ナトリウム１．４２ｇを正確に量り、蒸留水を加えて溶解後、全量を１００ｍＬとした（１００ｍＭリン酸水素二ナトリウム溶液）。リン酸二水素カリウム１．３６ｇを正確に量り、蒸留水を加えて溶解後、全量を１００ｍＬとした（１００ｍＭリン酸二水素カリウム溶液）。１００ｍＭリン酸水素二ナトリウム溶液に１００ｍＭリン酸二水素カリウム溶液を徐々に加えて、ｐＨを７．４にあわせた。
リン酸塩緩衝液の濃度が１００ｍＭ以下のものについては調製した１００ｍＭリン酸塩緩衝液ｐＨ７．４の溶液に蒸留水を加えることで希釈して調製した。
(2) Preparation of phosphate buffer solution 1.42 g of disodium hydrogen phosphate was accurately weighed and dissolved by adding distilled water, and the total amount was adjusted to 100 mL (100 mM disodium hydrogen phosphate solution). After accurately weighing 1.36 g of potassium dihydrogen phosphate and adding distilled water for dissolution, the total volume was made up to 100 mL (100 mM potassium dihydrogen phosphate solution). The 100 mM potassium dihydrogen phosphate solution was gradually added to the 100 mM disodium hydrogen phosphate solution to adjust the pH to 7.4.
Those having a phosphate buffer concentration of 100 mM or less were diluted by adding distilled water to the prepared 100 mM phosphate buffer pH 7.4 solution.
（３）Ｌ−アルギニン又はＬ−ヒスチジンを各々１０，２０，５０，１００、２００、３００および５００ｍｇを正確にバイアル瓶に秤量した。これら各バイアル瓶に、グリチルリチン酸モノアンモニウム塩１ｇを正確に加えた。１００ｍＭリン酸塩緩衝液約９ｍＬを加え６０℃で溶解後、室温に戻して１００ｍＭリン酸塩緩衝液を加えて全量を１０ｍＬとした。 (3) 10, 20, 50, 100, 200, 300 and 500 mg of L-arginine or L-histidine, respectively, were accurately weighed into vials. 1 g of glycyrrhizic acid monoammonium salt was accurately added to each of these vials. About 9 mL of 100 mM phosphate buffer was added and dissolved at 60 ° C., then returned to room temperature, and 100 mM phosphate buffer was added to make the total volume 10 mL.
（４）ゲル化温度の測定
前記（３）の操作により調製した試料を３０℃に設定した水浴に移した。水浴の温度を１０分間に１℃の割合で低下させ、試料がゲル化し始める温度を検討した。各試料のゲル化した温度を表１に示した。
(4) Measurement of gelation temperature The sample prepared by the operation of (3) was transferred to a water bath set at 30 ° C. The temperature of the water bath was decreased at a rate of 1 ° C. for 10 minutes, and the temperature at which the sample started to gel was examined. Table 1 shows the gelled temperature of each sample.
（５）前期（３）の操作により調製した試料の中で３℃においてゲルを形成しなかった試料のｐＨを測定した。各試料のｐＨ値を表１に示した。 (5) The pH of the sample that did not form a gel at 3 ° C. among the samples prepared by the operation in the previous period (3) was measured. The pH value of each sample is shown in Table 1.
（６）前期（３）の操作により調製した試料の中で３℃においてゲルを形成しなかった試料の浸透圧を測定した。各試料の浸透圧を表１に示した。 (6) The osmotic pressure of a sample that did not form a gel at 3 ° C. among the samples prepared by the operation in the previous period (3) was measured. The osmotic pressure of each sample is shown in Table 1.
（７）前期（３）の操作により調製した試料の中で３℃においてゲルを形成しなかった試料中のグリチルリチン酸モノアンモニウム塩の濃度を高速液体クロマトグラフィーを用いて測定した。各試料中のグリチルリチン酸モノアンモニウム塩の濃度を表１に示した。 (7) The concentration of monoammonium glycyrrhizinate in a sample that did not form a gel at 3 ° C. among the samples prepared by the operation in the previous period (3) was measured using high performance liquid chromatography. The concentration of monoammonium glycyrrhizinate in each sample is shown in Table 1.
（５）結果
１００ｍｇ／ｍＬのグリチルリチン酸モノアンモニウム塩水溶液にＬ−アルギニン又はＬ−ヒスチジンを加えることで、その添加量に比例してゲル化する温度が低下した。Ｌ−アルギニンおよびＬ−ヒスチジンともに濃度として１ｗ／ｖ％以上にすることで冷蔵保存においてもゲル形成しないことが明らかになった。
３℃でゲルを形成しなかった試料のｐＨ値は５．５〜８．０の範囲であった。
３℃でゲルを形成しなかった試料の浸透圧は３５７〜５７８ｍＯｓｍの範囲であった。
３℃でゲルを形成しなかった試料のグリチルリチン酸モノアンモニウム塩の濃度は９７．０ｍｇ／ｍＬ以上であった。
(5) Results By adding L-arginine or L-histidine to a 100 mg / mL aqueous solution of monoammonium glycyrrhizinate, the temperature at which gelation occurred was reduced in proportion to the amount added. It was clarified that no gel was formed even in refrigerated storage when the concentration of both L-arginine and L-histidine was 1 w / v% or more.
The pH value of the sample that did not form a gel at 3 ° C. was in the range of 5.5 to 8.0.
The osmotic pressure of the sample that did not form a gel at 3 ° C. was in the range of 357 to 578 mOsm.
The concentration of monoammonium glycyrrhizinate in the sample that did not form a gel at 3 ° C. was 97.0 mg / mL or more.
（１）実施例２で用いた機器は、次の通りである。
恒温槽（ＤＳ−６１、ヤマト）
ｐＨメーター（Ｄ−１４、堀場）
浸透圧計（ＯＭ−８０２Ｄ、ＶＯＧＥＬ）
高速液体クロマトグラフィー（６５５、日立）
(1) The equipment used in Example 2 is as follows.
Constant temperature bath (DS-61, Yamato)
pH meter (D-14, Horiba)
Osmometer (OM-802D, VOGEL)
High performance liquid chromatography (655, Hitachi)
（２）生理的条件であるｐＨ７．４付近、浸透圧比約１を満たすグリチルリチン酸モノアンモニウム塩溶液の調製
実施例１の結果をもとにして、生理的条件であるｐＨ７．４付近、浸透圧比約１（３００ｍＯｓｍ）を満たすグリチルリチン酸モノアンモニウム塩溶液の調製を試みた。浸透圧の調整はリン酸塩緩衝液の濃度を変えることでおこなった。ここではｐＨ調整剤の添加はおこなわなかった。
(2) Preparation of glycyrrhizic acid monoammonium salt solution that satisfies physiological conditions around pH 7.4 and osmotic pressure ratio of about 1 Based on the results of Example 1, physiological conditions around pH 7.4 and osmotic pressure ratio An attempt was made to prepare a glycyrrhizic acid monoammonium salt solution satisfying about 1 (300 mOsm). The osmotic pressure was adjusted by changing the phosphate buffer concentration. Here, no pH adjuster was added.
（３）処方１
Ｌ−アルギニン２００ｍｇおよびグリチルリチン酸モノアンモニウム塩１ｇを正確にバイアル瓶に秤量し、７０ｍＭリン酸塩緩衝液（ｐＨ７．４）を９ｍＬ加え、６０℃の恒温槽に３０分間放置し溶解させた。室温に戻した後、７０ｍＭリン酸塩緩衝液（ｐＨ７．４）を加えて全量を１０ｍＬとした。
（４）処方２
Ｌ−アルギニン３００ｍｇおよびグリチルリチン酸モノアンモニウム塩１ｇを正確にバイアル瓶に秤量し、５０ｍＭリン酸塩緩衝液（ｐＨ７．４）を９ｍＬ加え、６０℃の恒温槽に３０分間放置し溶解させた。室温に戻した後、５０ｍＭリン酸塩緩衝液（ｐＨ７．４）を加えて全量を１０ｍＬとした。
（５）処方３
Ｌ−アルギニン４５０ｍｇおよびグリチルリチン酸モノアンモニウム塩１ｇを正確にバイアル瓶に秤量し、３０ｍＭリン酸塩緩衝液（ｐＨ７．４）を９ｍＬ加え、６０℃の恒温槽に３０分間放置し溶解させた。室温に戻した後、３０ｍＭリン酸塩緩衝液（ｐＨ７．４）を加えて全量を１０ｍＬとした。
（６）処方４
Ｌ−ヒスチジン１００ｍｇおよびグリチルリチン酸モノアンモニウム塩１ｇを正確にバイアル瓶に秤量し、８０ｍＭリン酸塩緩衝液（ｐＨ７．４）を９ｍＬ加え、６０℃の恒温槽に３０分間放置し溶解させた。室温に戻した後、８０ｍＭリン酸塩緩衝液（ｐＨ７．４）を加えて全量を１０ｍＬとした。
（７）処方５
Ｌ−ヒスチジン２００ｍｇおよびグリチルリチン酸モノアンモニウム塩１ｇを正確にバイアル瓶に秤量し、５０ｍＭリン酸塩緩衝液（ｐＨ７．４）を９ｍＬ加え、６０℃の恒温槽に３０分間放置し溶解させた。室温に戻した後、５０ｍＭリン酸塩緩衝液（ｐＨ７．４）を加えて全量を１０ｍＬとした。
（８）処方６
Ｌ−ヒスチジン３００ｍｇおよびグリチルリチン酸モノアンモニウム塩１ｇを正確にバイアル瓶に秤量し、２０ｍＭリン酸塩緩衝液（ｐＨ７．４）を９ｍＬ加え、６０℃の恒温槽に３０分間放置し溶解させた。室温に戻した後、２０ｍＭリン酸塩緩衝液（ｐＨ７．４）を加えて全量を１０ｍＬとした。
(3) Formula 1
200 mg of L-arginine and 1 g of glycyrrhizic acid monoammonium salt were accurately weighed in a vial, 9 mL of 70 mM phosphate buffer (pH 7.4) was added, and the mixture was allowed to stand for 30 minutes in a constant temperature bath at 60 ° C. to dissolve. After returning to room temperature, 70 mM phosphate buffer (pH 7.4) was added to make the total volume 10 mL.
(4) Formula 2
L-arginine (300 mg) and glycyrrhizic acid monoammonium salt (1 g) were accurately weighed in a vial, added with 9 mL of 50 mM phosphate buffer (pH 7.4), and allowed to stand for 30 minutes in a constant temperature bath at 60 ° C. to dissolve. After returning to room temperature, 50 mM phosphate buffer (pH 7.4) was added to make the total volume 10 mL.
(5) Formula 3
450 mg of L-arginine and 1 g of glycyrrhizic acid monoammonium salt were accurately weighed in a vial, 9 mL of 30 mM phosphate buffer (pH 7.4) was added, and the mixture was allowed to stand for 30 minutes in a constant temperature bath at 60 ° C. to dissolve. After returning to room temperature, 30 mM phosphate buffer (pH 7.4) was added to make the total volume 10 mL.
(6) Formula 4
L-histidine (100 mg) and glycyrrhizic acid monoammonium salt (1 g) were accurately weighed into a vial, 9 mL of 80 mM phosphate buffer (pH 7.4) was added, and the mixture was allowed to stand in a 60 ° C. constant temperature bath for 30 minutes for dissolution. After returning to room temperature, 80 mM phosphate buffer (pH 7.4) was added to make the total volume 10 mL.
(7) Formula 5
L-histidine (200 mg) and glycyrrhizic acid monoammonium salt (1 g) were accurately weighed in a vial, 9 mL of 50 mM phosphate buffer (pH 7.4) was added, and the mixture was allowed to stand in a constant temperature bath at 60 ° C. for 30 minutes for dissolution. After returning to room temperature, 50 mM phosphate buffer (pH 7.4) was added to make the total volume 10 mL.
(8) Formula 6
L-histidine (300 mg) and glycyrrhizic acid monoammonium salt (1 g) were accurately weighed in a vial, 9 mL of 20 mM phosphate buffer (pH 7.4) was added, and the mixture was allowed to stand in a constant temperature bath at 60 ° C. for 30 minutes for dissolution. After returning to room temperature, 20 mM phosphate buffer (pH 7.4) was added to make the total volume 10 mL.
処方１〜処方６のｐＨおよび浸透圧を測定した。各試料のｐＨ値および浸透圧を表２に示した。 The pH and osmotic pressure of Formula 1 to Formula 6 were measured. The pH value and osmotic pressure of each sample are shown in Table 2.
（９）グリチルリチン酸モノアンモニウム塩の安定性
処方１〜処方６の各試料を４℃、４０℃および６０℃に設定した恒温槽に保管し、２週間後のグリチルリチン酸モノアンモニウム塩の濃度を高速液体クロマトグラフィーを用いて測定した。各処方調製直後のグリチルリチン酸モノアンモニウム塩の濃度を１００としたときの残存率（平均値±標準偏差）を表２に示した。
(9) Stability of glycyrrhizic acid monoammonium salt Each sample of Formulations 1 to 6 was stored in a constant temperature bath set at 4 ° C, 40 ° C and 60 ° C, and the concentration of glycyrrhizic acid monoammonium salt after 2 weeks was high speed. Measurement was performed using liquid chromatography. Table 2 shows the residual ratio (average value ± standard deviation) when the concentration of glycyrrhizic acid monoammonium salt immediately after preparation of each formulation was taken as 100.
（１０）結果
処方２および処方３は限りなく生理的条件であるｐＨ７．４、浸透圧比約１に近かった。処方１、処方４〜６のｐＨ値は酸性側に偏ってはいるが、ｐＨ調整剤の添加によりｐＨ７．４付近に近づけることが可能である。安定性の検討より、６０℃、２週間の保存においても残存率が９８％以上であった。これらの結果は、Ｌ−アルギニンあるいはＬ−ヒスチジンを添加物として用いた場合、それらの共存下においてもグリチルリチン酸が安定に存在することを示す。
(10) Results Formulas 2 and 3 were infinitely close to the physiological conditions of pH 7.4 and osmotic pressure ratio of about 1. Although the pH values of Formula 1 and Formulas 4 to 6 are biased toward the acidic side, it can be brought close to pH 7.4 by adding a pH adjuster. From the examination of stability, the residual rate was 98% or more even after storage at 60 ° C. for 2 weeks. These results indicate that when L-arginine or L-histidine is used as an additive, glycyrrhizic acid is stably present even in the presence thereof.
本発明のグリチルリチン酸又はその塩の高濃度水溶液は、安全性の面で支障のない添加物を用いることでその調製が可能になった。慢性肝疾患の患者に対してこれまで処方されてきた静脈内への大量投与に変わる製剤、例えば少量の静脈内投与、筋肉内投与、皮下投与製剤として容易にしかも迅速に処方化が可能になる。 The high-concentration aqueous solution of glycyrrhizic acid or a salt thereof of the present invention can be prepared by using an additive that does not hinder the safety. A formulation that can be easily and quickly formulated as a preparation that can be used in patients with chronic liver disease instead of the conventional high-dose intravenous administration, such as small-volume intravenous, intramuscular, or subcutaneous administration. .
Claims (6)
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| JP2005234191A JP2007045788A (en) | 2005-08-12 | 2005-08-12 | Method for preparing aqueous solution of glycyrrhizinic acid having high concentration |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014119614A1 (en) * | 2013-01-30 | 2014-08-07 | 宏輝システムズ株式会社 | Soft tablet orally-administered preparation |
| JP2020525499A (en) * | 2017-06-30 | 2020-08-27 | オンクセオＯｎｘｅｏ | New oral formulation of berynostat |
| JP2021524259A (en) * | 2018-05-25 | 2021-09-13 | クヴェッラ コーポレーション | Methods and Compositions for Selective Lysis of Blood Cells and Separation of Microbial Cells |
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2005
- 2005-08-12 JP JP2005234191A patent/JP2007045788A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014119614A1 (en) * | 2013-01-30 | 2014-08-07 | 宏輝システムズ株式会社 | Soft tablet orally-administered preparation |
| JP2020525499A (en) * | 2017-06-30 | 2020-08-27 | オンクセオＯｎｘｅｏ | New oral formulation of berynostat |
| JP7247122B2 (en) | 2017-06-30 | 2023-03-28 | アクロテック バイオファーマ リミティド ライアビリティ カンパニー | New Oral Formulation of Belinostat |
| JP2021524259A (en) * | 2018-05-25 | 2021-09-13 | クヴェッラ コーポレーション | Methods and Compositions for Selective Lysis of Blood Cells and Separation of Microbial Cells |
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