JPH0959162A - Gallstone dissolving agent - Google Patents
Gallstone dissolving agentInfo
- Publication number
- JPH0959162A JPH0959162A JP21838095A JP21838095A JPH0959162A JP H0959162 A JPH0959162 A JP H0959162A JP 21838095 A JP21838095 A JP 21838095A JP 21838095 A JP21838095 A JP 21838095A JP H0959162 A JPH0959162 A JP H0959162A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- hours
- gallstone
- ursodeoxycholic acid
- compound
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、胆石溶解剤に関する。
更に詳しくは、ウルソデオキシコール酸アミノクエン酸
及びそのナトリウム塩を有効成分として含有する胆石溶
解剤に関する。TECHNICAL FIELD The present invention relates to a gallstone dissolving agent.
More specifically, it relates to a gallstone dissolving agent containing ursodeoxycholic acid aminocitric acid and its sodium salt as an active ingredient.
【０００２】[0002]
【従来の技術】食生活の欧米化に伴い、わが国の胆石保
有率は約１０％におよび、胆石症は日常臨床上遭遇する
頻度の高い消化器疾患の一つになっていると報告され、
胆石溶解療法は胆嚢温存・非侵襲的治療法として確立さ
れてきている。胆石はその成分によりコレステロール結
石と色素石（ビリルビンカルシウムと黒色石）に大別さ
れている。胆石溶解剤として繁用されている薬物として
は、ウルソデオキシコール酸及びケノデオキシコール酸
が知られているが、これらの胆汁酸は、純コレステロー
ル石に対しては有効であるが、他のコレステロール石、
たとえばカルシウムを含有するコレステロール混成石ま
たはコレステロール混合石、さらには、ビリルビンカル
シウム石または炭酸カルシウム石等に対しては、その溶
解効果が疑問視されている。2. Description of the Related Art With the westernization of dietary habits, the gallstone ownership rate in Japan has reached approximately 10%, and gallstone disease is reported to be one of the most frequently encountered gastrointestinal disorders in clinical practice.
Cholelithilytic therapy has been established as a gallbladder-sparing and non-invasive treatment method. Gallstones are roughly classified into cholesterol stones and pigment stones (bilirubin calcium and black stone) according to their components. As drugs commonly used as gallstone solubilizers, ursodeoxycholic acid and chenodeoxycholic acid are known.These bile acids are effective against pure cholesterol stones, but other cholesterol stones are also known.
For example, a cholesterol-mixing stone or a cholesterol-mixing stone containing calcium, and further bilirubin calcium stone, calcium carbonate stone, and the like have been questioned for their dissolving effect.
【０００３】[0003]
【発明が解決しようとする課題】上記事情の下で、カル
シウムを含有するコレステロール混成石またはコレステ
ロール混合石、さらには、ビリルビンカルシウム石また
は炭酸カルシウム石等に対して溶解効果のある薬剤の開
発が望まれていた。Under the above circumstances, it is desired to develop a drug having a dissolving effect on cholesterol-containing mixed stones or mixed stones containing calcium, and further bilirubin calcium stones or calcium carbonate stones. It was rare.
【０００４】[0004]
【課題を解決するための手段】かくして、本発明者は、
臨床において第一選択とされることの多い、ウルソデオ
キシコール酸の誘導体について研究中に、ウルソデオキ
シコール酸アミノクエン酸及びそのナトリウム塩が優れ
た胆石溶解作用を持つことを見いだし、本発明を完成さ
せた。Thus, the present inventor has
In the course of research on derivatives of ursodeoxycholic acid, which is often the first choice in the clinic, we found that aminocitric acid ursodeoxycholic acid and its sodium salt have an excellent gallstone-dissolving effect, and completed the present invention. Let
【０００５】本発明の化合物は、モノアミノトリカルボ
ン酸とウルソデオキシコール酸を反応することにより製
造することができる。The compound of the present invention can be produced by reacting monoaminotricarboxylic acid with ursodeoxycholic acid.
【０００６】すなわち、冷却したメタノ−ルまたはエタ
ノールにチオニルクロライドを添加した後、モノアミノ
カルボン酸を加え、−１０℃〜５０℃、好ましくは３０
〜４０℃で、５〜４８時間、好ましくは２４〜４８時間
攪拌し、濃縮してモノアミノカルボン酸のエステル体を
得る。That is, thionyl chloride is added to cooled methanol or ethanol, and then monoaminocarboxylic acid is added thereto, and the temperature is -10 ° C to 50 ° C, preferably 30 ° C.
The mixture is stirred at -40 ° C for 5 to 48 hours, preferably 24 to 48 hours, and concentrated to obtain a monoaminocarboxylic acid ester.
【０００７】一方、ウルソデオキシコール酸はトリエチ
ルアミン、トリプロピルアミンまたはトリ−ｎ−ブチル
アミンを含有するジオキサン、ＴＨＦ等の環状エーテル
に懸濁し、エチルクロロカルボン酸を加えて更に攪拌
し、引き続きトリ−ｎ−ブチルアミンに懸濁したモノア
ミノカルボン酸のエステル体と混合し、３０〜４０℃
で、１５〜２４時間攪拌下反応させる。反応液を濃縮
後、シリカゲルクロマトグラフィー（クロロホルム：メ
タノール＝１５：１〜５：１）により分画し、得られた
ジメチルエステル体を加水分解後、１Ｎ塩酸でｐＨ１と
して、酢酸エチル抽出を行い、酢酸エチル層を濃縮、結
晶化してウルソデオキシコール酸−２−アミノクエン酸
を得る。On the other hand, ursodeoxycholic acid is suspended in a cyclic ether such as dioxane or THF containing triethylamine, tripropylamine or tri-n-butylamine, ethylchlorocarboxylic acid is added and the mixture is further stirred, and then tri-n is added. -Mixed with monoaminocarboxylic acid ester suspended in butylamine, 30-40 ° C
Then, the reaction is carried out with stirring for 15 to 24 hours. After the reaction solution was concentrated, it was fractionated by silica gel chromatography (chloroform: methanol = 15: 1 to 5: 1), the obtained dimethyl ester was hydrolyzed, and the pH was adjusted to 1 with 1N hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate layer is concentrated and crystallized to obtain ursodeoxycholic acid-2-aminocitric acid.
【０００８】更に、ウルソデオキシコール酸−２−アミ
ノクエン酸を水に溶解し１Ｎ水酸化ナトリウムによりｐ
Ｈ１１にしたものを、合成吸着剤（ＨＰ−２０）カラム
を通し、メタノールで溶出することによってウルソデオ
キシコール酸−２−アミノクエン酸３ナトリウム塩を得
ることができる。Further, ursodeoxycholic acid-2-aminocitric acid was dissolved in water and p-ionized with 1N sodium hydroxide.
Ursodeoxycholic acid-2-aminocitric acid trisodium salt can be obtained by passing the H11-containing product through a synthetic adsorbent (HP-20) column and eluting with methanol.
【０００９】以下に、本発明化合物のカルシウム溶解
性、胆汁移行性、吸収性及び安定性について、ウルソデ
オキシコール酸−２−アミノクエン酸３ナトリウム（以
下ＵＤＣＡクエン酸３Ｎａとする）を用いて説明する。The calcium solubility, bile transportability, absorbability and stability of the compound of the present invention will be described below using trisodium ursodeoxycholic acid-2-aminocitrate (hereinafter referred to as UDCA citrate 3Na). To do.
【００１０】（１）胆汁排泄率 ウイスタ−系ラットに３０ｍｇ／ｋｇのＵＤＣＡクエン
酸３Ｎａを静脈内投与した後、経時的に胆汁を採取しそ
の胆汁排泄率をＨＰＬＣ（３α−ＨＳＤ固定化酵素カラ
ムを用いた蛍光検出法）により測定した。結果を表１に
示す。(1) Bile excretion rate After Wistar rats were intravenously administered with 30 mg / kg of UDCA 3Na citrate, bile was collected over time and the bile excretion rate was determined by HPLC (3α-HSD immobilized enzyme column). Fluorescence detection method). The results are shown in Table 1.
【００１１】[0011]
【表１】 [Table 1]
【００１２】投与後１時間で４９．２％の胆汁排泄率を
示し、胆汁への移行性が優れていることが示唆された。Bile excretion rate of 49.2% was shown 1 hour after administration, suggesting that the transferability to bile is excellent.
【００１３】（２）反転腸管モデルを用いた吸収性の検
討 １２−２４時間絶食したラットを脱血死させた後、回腸
部を取り出し内腔を生理食塩水にて３回よく洗浄する。
上部と下部に分割し、各セグメントの中ほど１０ｃｍを
実験に用いた。ＵＤＣＡクエン酸３Ｎａのほかに対照と
して、タウロコール酸ナトリウムを用いた。(2) Examination of absorbability using inverted intestinal tract model After the rats fasted for 12 to 24 hours were exsanguinated to death by blood removal, the ileum was removed and the lumen was thoroughly washed with physiological saline three times.
It was divided into an upper part and a lower part, and 10 cm in the middle of each segment was used for the experiment. In addition to UDCA 3Na citrate, sodium taurocholate was used as a control.
【００１４】０．３％グルコース含有クレブス−リンゲ
ル重炭酸緩衝液（ｐＨ７．４）に本発明化合物またはタ
ウロコール酸ナトリウムを溶解した溶液（終濃度０．１
ｍＭ）を袋状にした各セグメント及びフラスコに入れ、
袋状にした各セグメントは同一溶液を入れたフラスコ中
に入れて、ＣＯ2 −Ｏ2 （９５：５）ガスを吹き込みな
がら３７℃で１時間インキュベートした。インキュベー
ト後の反転腸管内外の胆汁酸濃度を測定し、外液中濃度
に対する内液中濃度の比を算出した。結果を表２に示し
た。A solution of the compound of the present invention or sodium taurocholate in Krebs-Ringer's bicarbonate buffer (pH 7.4) containing 0.3% glucose (final concentration 0.1).
(mM) into each bag-shaped segment and flask,
Each bag-shaped segment was placed in a flask containing the same solution, and incubated at 37 ° C. for 1 hour while blowing CO 2 —O 2 (95: 5) gas. After the incubation, the bile acid concentration inside and outside the inverted intestinal tract was measured, and the ratio of the concentration in the inner fluid to the concentration in the outer fluid was calculated. The results are shown in Table 2.
【００１５】[0015]
【表２】 [Table 2]
【００１６】回腸下部での比が１以上の値を示し、本発
明化合物はタウロコール酸と同様に能動的に吸収されて
いることが示唆された。The ratio in the lower ileum showed a value of 1 or more, suggesting that the compound of the present invention is actively absorbed in the same manner as taurocholic acid.
【００１７】（３）酵素安定性−１ ＵＤＣＡクエン酸３Ｎａのトリプシン活性人膵液酵素に
対する安定性を検討した。(3) Enzyme Stability-1 The stability of UDCA 3Na citrate against trypsin active human pancreatic juice enzyme was examined.
【００１８】ＵＤＣＡクエン酸３Ｎａの他にhippury-L-
phenylalanine(CPA),benzoly-L-arginine-p-nitroanili
de(BANA)を基質として用いた。In addition to UDCA 3Na citrate, hippury-L-
phenylalanine (CPA), benzoly-L-arginine-p-nitroanili
de (BANA) was used as a substrate.
【００１９】終濃度１ｍＭになるように０．０５Ｍ Ｍ
ＯＰＳ緩衝液（ｐＨ７．０）で調製した各基質２．４ｍ
ｌにトリプシン活性人膵液酵素液０．６ｍｌを加えて、
３７℃で４８時間インキュベートした。途中０．５，
１，２，１２，２４時間で各試料を３００μｌ採取した
後、９倍量のエタノールを添加することにより反応を停
止し、ＴＬＣ（ＥｔＯＨ：ＮＨ4 ＯＨ＝３：１）にて反
応生成物の確認を行った。0.05M M so that the final concentration is 1 mM
2.4 m of each substrate prepared with OPS buffer (pH 7.0)
0.6 ml of trypsin active human pancreatic juice enzyme solution was added to 1
Incubated at 37 ° C for 48 hours. 0.5 on the way
After 300 μl of each sample was collected at 1, 2, 12 and 24 hours, the reaction was stopped by adding 9 volumes of ethanol, and the reaction product was analyzed by TLC (EtOH: NH 4 OH = 3: 1). I confirmed.
【００２０】反応０．５時間及び４８時間の各試料のＴ
ＬＣ挙動を図１に示した。T of each sample at 0.5 hour and 48 hour reaction
The LC behavior is shown in Figure 1.
【００２１】本発明化合物は４８時間後においても膵酵
素によって水解されなかった。 （４）酵素安定性−２ ＵＤＣＡクエン酸３Ｎａのコリルグリシンヒドロラ−ゼ
に対する安定性をＮａｉｒらの方法（P.P.Nair:Enzymat
ic cleavage of bile acid conjugates,"BileSalt Meta
bolism,"ed.by L.Schiff,T.B.Carey,J.R.Dietschy, and
J.M.Dietschy,C C Thomas Springfield,lll,USA,1969,
pp.172-183 ）により検討した。The compound of the present invention was not hydrolyzed by the pancreatic enzyme even after 48 hours. (4) Enzyme Stability-2 The stability of UDCA 3Na citrate against chorylglycine hydrolase was determined by the method of Nair et al. (PPNair: Enzymat).
ic cleavage of bile acid conjugates, "BileSalt Meta
bolism, "ed.by L.Schiff, TBCarey, JRDietschy, and
JMDietschy, CC Thomas Springfield, lll, USA, 1969,
pp.172-183).
【００２２】すなわち、０．０２５Ｍ酢酸ナトリウム緩
衝液２ｍｌ，同緩衝液に溶解した本発明化合物（終濃
度：０．５，０．７５，１．０，１．５，２．０ｍＭ）
１．５ｍｌ、１．５６％２−メルカプトエタノール溶液
０．５ｍｌ、３．２７％ＥＤＴＡ溶液０．５ｍｌ、及
び、コリルグリシンヒドロラーゼ溶液（終濃度４ユニッ
ト）０．５ｍｌからなる反応液を３７℃で２４時間イン
キュベートした。反応途中（１，２，３，１８時間）で
各試料を２００μｌ採取した後、９倍量のエタノールを
添加することにより反応を停止し、遠心後、上清をとり
濃縮後、ＴＬＣ（ＥｔＯＨ：ＮＨ4 ＯＨ＝３：１）にて
反応生成物の確認を行った。対照としてグリココール酸
を基質として、同様の反応を行った。That is, 2 ml of 0.025 M sodium acetate buffer, the compound of the present invention dissolved in the same buffer (final concentration: 0.5, 0.75, 1.0, 1.5, 2.0 mM)
A reaction liquid consisting of 1.5 ml, 0.56 ml of 1.56% 2-mercaptoethanol solution, 0.5 ml of 3.27% EDTA solution, and 0.5 ml of chorylglycine hydrolase solution (final concentration 4 units) at 37 ° C. Incubated for 24 hours. After collecting 200 μl of each sample during the reaction (1, 2, 3, 18 hours), the reaction was stopped by adding 9 volumes of ethanol, and after centrifugation, the supernatant was collected and concentrated, followed by TLC (EtOH: The reaction product was confirmed with NH 4 OH = 3: 1). As a control, the same reaction was performed using glycocholic acid as a substrate.
【００２３】基質濃度２ｍＭの時のＴＬＣ結果を図２に
示した。The TLC results at a substrate concentration of 2 mM are shown in FIG.
【００２４】ＵＤＣＡクエン酸３Ｎａは、１８時間経過
しても１０％以下がＵＤＣＡとなるだけで、グリココー
ル酸に比較してコリルグリシンヒドロラーゼに対し抵抗
性を有していた。UDCA 3Na citrate was more resistant to cholylglycine hydrolase than glycocholate, only 10% or less of UDCA remained after 18 hours.
【００２５】（５）カルシウム溶解能 胆汁酸の０．０１Ｍリン酸塩緩衝液（ｐＨ６．５，７．
４及び８．５）２ｍｌに炭酸カルシウム４ｍｇを加え
て、室温で１３時間振盪した。その後、３０００ｒｐｍ
で１５分間遠心分離し、上澄液をクロマトディスクでろ
過し、ろ液を０．１Ｎ塩酸で希釈後原子吸光光度計を用
い、ろ液中のカルシウム濃度を測定した。結果を表３に
示した。(5) Calcium solubility A 0.01M phosphate buffer solution of bile acid (pH 6.5, 7.
4 and 8.5) 2 mg of calcium carbonate was added to 2 ml, and the mixture was shaken at room temperature for 13 hours. After that, 3000 rpm
After centrifuging for 15 minutes, the supernatant was filtered through a chromatographic disk, the filtrate was diluted with 0.1N hydrochloric acid, and the calcium concentration in the filtrate was measured using an atomic absorption spectrophotometer. The results are shown in Table 3.
【００２６】[0026]
【表３】 [Table 3]
【００２７】ＵＤＣＡクエン酸３Ｎａのカルシウム溶解
性は、ｐＨ８．５では０．２１ｍｇ／ｄｌであったが、
ｐＨ６．５では３．７６ｍｇ／ｄｌと、酸性度が増すに
従い、溶解性が上昇した。The calcium solubility of UDCA 3Na citrate was 0.21 mg / dl at pH 8.5,
At pH 6.5, the solubility increased to 3.76 mg / dl as the acidity increased.
【００２８】一般に、肝胆汁のｐＨ（７．１−８．５）
に比して，胆嚢胆汁のｐＨは低い（５．５−７．７）と
報告されている。したがって、本発明化合物は弱酸性ｐ
Ｈでカルシウム溶解能を有することから、胆嚢中に生成
するカルシウムを含有するコレステロール混成石または
コレステロール混合石、さらには、ビリルビンカルシウ
ム石または炭酸カルシウム石等に対して溶解効果が期待
できる。Generally, the pH of the liver and bile (7.1-8.5)
It is reported that the pH of gallbladder bile is lower (5.5-7.7) than that of the above. Therefore, the compound of the present invention is slightly acidic p
Since it has a calcium-dissolving ability in H, it can be expected to have a dissolving effect on cholesterol mixed stones or cholesterol mixed stones containing calcium produced in the gallbladder, and further on bilirubin calcium stones or calcium carbonate stones.
【００２９】本発明化合物を胆石溶解剤として患者に投
与する際は、経口投与若しくは非経口投与（筋肉内，皮
下，静脈内，坐薬等）により投与されるが、通常は経口
投与される。投与量は、年齢、症状により異なるが、ウ
ルソデオキシコール酸アミノクエン酸の量として、通常
成人１日あたり５０〜３０００ｍｇ、好ましくは２５０
〜１５００ｍｇを経口で用いる。本発明の化合物を製剤
化するためには、製剤の技術分野における通常の方法で
錠剤、顆粒剤、散剤、カプセル剤、注射剤及び坐薬等の
剤型とする。When the compound of the present invention is administered to a patient as a gallstone dissolving agent, it is administered orally or parenterally (intramuscularly, subcutaneously, intravenously, suppository, etc.), but usually it is orally administered. Although the dose varies depending on age and symptoms, the amount of ursodeoxycholic acid aminocitrate is usually 50 to 3000 mg, preferably 250 per adult per day.
~ 1500 mg is used orally. In order to formulate the compound of the present invention, it is made into a dosage form such as a tablet, a granule, a powder, a capsule, an injection and a suppository by a conventional method in the technical field of preparation.
【００３０】すなわち、経口用固形製剤を調剤する場合
は、主薬に賦形剤、更に必要に応じて結合剤、崩壊剤、
滑沢剤、着色剤、矯味矯臭剤等を加えた後、錠剤、被覆
錠剤、顆粒剤、散剤、カプセル剤等とする。That is, in the case of preparing a solid preparation for oral administration, an excipient is added to the main drug, and if necessary, a binder, a disintegrant,
After adding a lubricant, a coloring agent, a flavoring agent and the like, tablets, coated tablets, granules, powders, capsules and the like are prepared.
【００３１】以下に、本発明の内容を実施例により詳細
に説明する。The contents of the present invention will be described in detail below with reference to examples.
【００３２】[0032]
実施例１（ウルソデオキシコール酸アミノクエン酸の合
成） −１０℃に冷却したメタノ−ル５ｍｌにチオニルクロラ
イド１ｍｌを少量ずつ滴下し、モノアミノカルボン酸２
００ｍｇを加え、３７℃で４８時間攪拌した後、濃縮、
メタノール洗浄（２回）してモノアミノカルボン酸メチ
ルエステル体を得た。Example 1 (Synthesis of ursodeoxycholic acid aminocitric acid) To 5 ml of methanol cooled to -10 ° C, 1 ml of thionyl chloride was added dropwise little by little to give monoaminocarboxylic acid 2
00 mg was added, and the mixture was stirred at 37 ° C for 48 hours, then concentrated,
Methanol washing (twice) gave a monoaminocarboxylic acid methyl ester form.
【００３３】トリ−ｎ−ブチルアミン９００μｌに懸濁
したモノアミノカルボン酸メチルエステル体に、ウルソ
デオキシコール酸３１４ｍｇをジオキサン２ｍｌとトリ
−ｎ−ブチルアミン２９５μｌに加えて１０℃で攪拌し
ながら、エチルクロロカルボン酸１１９μｌを加えて更
に３０分攪拌したものを混合し、３７℃で攪拌しながら
２４時間反応させた。To a monoaminocarboxylic acid methyl ester suspension suspended in 900 μl of tri-n-butylamine, 314 mg of ursodeoxycholic acid was added to 2 ml of dioxane and 295 μl of tri-n-butylamine and stirred at 10 ° C. with ethylchlorocarboxylic acid. After adding 119 μl of acid and stirring for 30 minutes, the mixture was mixed and reacted at 37 ° C. for 24 hours while stirring.
【００３４】反応液を濃縮後、シリカゲルクロマトグラ
フィー（クロロホルム：メタノール＝１５：１〜５：
１）により分画した。After concentrating the reaction solution, silica gel chromatography (chloroform: methanol = 15: 1 to 5:
It fractionated by 1).
【００３５】得られたジメチルエステル体を加水分解
（５％水酸化ナトリウム−８０％メタノール溶液を加
え、６０℃で約３時間還流する）後、１Ｎ塩酸でｐＨ１
として、酢酸エチル抽出を行う。酢酸エチル層を濃縮
後、メタノールを用いて結晶化を行った。After the obtained dimethyl ester was hydrolyzed (5% sodium hydroxide-80% methanol solution was added and refluxed at 60 ° C. for about 3 hours), the pH was adjusted to 1 with 1N hydrochloric acid.
Then, ethyl acetate extraction is performed. The ethyl acetate layer was concentrated and then crystallized using methanol.
【００３６】ＭＳ（ＳＩＭＳ）：m/z 566(M+H)+ ＩＲ（KBr,cm-1）νmax ：3400(OH),2936,2868(CH),262
2(COOH),1732,1715(CO), 1652(CONH) １Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6 ）δppm ：0.608(3H,18-
CH3 ），0.872(3H,19-CH3 ）, 0.872 （3H,21-CH3 ），
2.919 〜3.082 （4H, クエン酸のCH2 ），3.328(2H,3β
-H,7α-H),3.869(1H、7β-OH),4.444(1H、 3α-OH),7.720
(1H,NH),12.000〜13.000(3H、 COOH ) 。MS (SIMS): m / z 566 (M + H) + IR (KBr, cm -1 ) ν max : 3400 (OH), 2936, 2868 (CH), 262
2 (COOH), 1732,1715 (CO), 1652 (CONH) 1H-NMR (DMSO-d 6 ) δppm: 0.608 (3H, 18-
CH 3 ), 0.872 (3H, 19-CH 3 ), 0.872 (3H, 21-CH 3 ),
2.919 ~ 3.082 (4H, CH 2 of citric acid), 3.328 (2H, 3β
-H, 7α-H), 3.869 (1H, 7β-OH), 4.444 (1H, 3α-OH), 7.720
(1H, NH), 12.000-13.000 (3H, COOH).
【００３７】実施例２（ウルソデオキシコール酸アミノ
クエン酸３ナトリウムの製造） 実施例１と同様にして得た酢酸エチル濃縮物を水（３０
ｍｌ）に溶解した後、１Ｎ ＮａＯＨでｐＨ１１に調整
し、合成吸着剤（ＨＰ−２０）カラムを通し、メタノー
ル（１００ｍｌ）で溶出した。溶出液を濃縮後、メタノ
ール及び酢酸エチルを用いて結晶化を行い、ウルソデオ
キシコール酸−２−アミノクエン酸３ナトリウム塩を得
た。Example 2 (Production of ursodeoxycholic acid trisodium aminocitrate) An ethyl acetate concentrate obtained in the same manner as in Example 1 was treated with water (30
After being dissolved in 1 ml of NaOH, the pH was adjusted to 11 with 1N NaOH, and the mixture was passed through a synthetic adsorbent (HP-20) column and eluted with methanol (100 ml). The eluate was concentrated and then crystallized using methanol and ethyl acetate to obtain ursodeoxycholic acid-2-aminocitric acid trisodium salt.
【００３８】[0038]
【発明の効果】本発明によれば、人膵液酵素やコリルグ
リシンハイドラーゼに対し抵抗性を有し、経口吸収性に
優れた、特に胆汁中で効果を発揮するカルシウム胆石溶
解用医薬組成物が提供される。INDUSTRIAL APPLICABILITY According to the present invention, there is provided a pharmaceutical composition for dissolving calcium gallstones, which is resistant to human pancreatic juice enzyme and chorylglycine hydrolase and is excellent in oral absorbability, and particularly effective in bile. Provided.
【図１】トリプシン活性を有する人膵液で処理した時の
反応生成物の挙動を示すＴＬＣ図である。FIG. 1 is a TLC diagram showing the behavior of reaction products when treated with human pancreatic juice having trypsin activity.
【図２】コリルグリシンヒドラーゼで処理した時の反応
生成物の挙動を示すＴＬＣ図である。FIG. 2 is a TLC diagram showing the behavior of reaction products when treated with cholylglycine hydrolase.
Claims (2)
ール酸アミノクエン酸またはそのナトリウム塩を有効成
分とする胆石溶解剤 【化１】 1. A gallstone dissolving agent containing ursodeoxycholic acid aminocitric acid represented by the following chemical formula or its sodium salt as an active ingredient.
３ナトリウムを有効成分とする請求項１記載の胆石溶解
剤2. The gallstone dissolving agent according to claim 1, which comprises trisodium ursodeoxycholic acid aminocitrate as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21838095A JPH0959162A (en) | 1995-08-28 | 1995-08-28 | Gallstone dissolving agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21838095A JPH0959162A (en) | 1995-08-28 | 1995-08-28 | Gallstone dissolving agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0959162A true JPH0959162A (en) | 1997-03-04 |
Family
ID=16718999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21838095A Pending JPH0959162A (en) | 1995-08-28 | 1995-08-28 | Gallstone dissolving agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0959162A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002528460A (en) * | 1998-10-28 | 2002-09-03 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Bile acid-substituted phenylalkenoylguanidines, their production, their use as drugs or diagnostics, and drugs containing them |
| JP2009530399A (en) * | 2006-03-22 | 2009-08-27 | シンデクサ ファーマシューティカルズ コーポレーション | Compounds and methods for the treatment of diseases associated with ER stress |
-
1995
- 1995-08-28 JP JP21838095A patent/JPH0959162A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002528460A (en) * | 1998-10-28 | 2002-09-03 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Bile acid-substituted phenylalkenoylguanidines, their production, their use as drugs or diagnostics, and drugs containing them |
| JP2009530399A (en) * | 2006-03-22 | 2009-08-27 | シンデクサ ファーマシューティカルズ コーポレーション | Compounds and methods for the treatment of diseases associated with ER stress |
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