JPH0367079B2 - - Google Patents
Info
- Publication number
- JPH0367079B2 JPH0367079B2 JP1829484A JP1829484A JPH0367079B2 JP H0367079 B2 JPH0367079 B2 JP H0367079B2 JP 1829484 A JP1829484 A JP 1829484A JP 1829484 A JP1829484 A JP 1829484A JP H0367079 B2 JPH0367079 B2 JP H0367079B2
- Authority
- JP
- Japan
- Prior art keywords
- ursodeoxycholic acid
- salt
- meglumine
- injection
- solution
- 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.)
- Expired
Links
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 18
- 229960001661 ursodiol Drugs 0.000 claims description 18
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- -1 Ursodeoxycholic acid meglumine salt Chemical class 0.000 claims description 10
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 8
- 229960003194 meglumine Drugs 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000731 choleretic agent Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940014499 ursodeoxycholate Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【発明の詳細な説明】
本発明はウルソデオキシコール酸メグルミン塩
およびその注射液に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ursodeoxycholic acid meglumine salt and its injection solution.
ウルソデオキシコール酸は利胆剤、胆石溶解剤
として広く用いられている医薬品であるが、水に
はほとんど溶解せず、これを水溶液にするため、
特に注射液とするため従来研究されてきた。 Ursodeoxycholic acid is a drug widely used as a choleretic agent and a gallstone dissolving agent, but it is hardly soluble in water, and in order to make it into an aqueous solution,
In particular, it has been studied to be used as an injection solution.
ウルソデオキシコール酸のナトリウム塩はPH
9.0〜11.0で20％以上水に溶解するがこの水溶液
は加熱または貯蔵に対して不安定である。これを
解決するためナトリウム塩水溶液に界面活性剤お
よびクエン酸を添加して安定化する方法が提案さ
れているが（特公昭35−17149号公報）、この場合
製造時PHを9.5〜11.0に調整しなければ完全に溶
解せず、PHが高いため保存中にアンプルガラス内
面からアルカリフレツクスが析出する欠点があつ
た。また、プロピレングリコールなどを溶剤とし
て用い、クエン酸塩およびアルカリを添加してPH
7.0〜8.0とする方法が知られているが（特公昭48
−37813号）、この方法ではプロピレングリコール
などの有機溶剤を高濃度で用いるため注射液の浸
透圧が著しく高くなり、その使用に当つて制限が
大きいという欠点がある。ウルソデオキシコール
酸をエタノールアミン塩とし、その水溶液に界面
活性剤を添加して製造時PH9.0で完全に溶解する
方法が公知であるが（特公昭48−37814号公報）、
界面活性剤の加水分解が避けられず、加熱滅菌処
理または経時により注射液の安定性が低下する。
またウルソデオキシコール酸をピペラジンとの塩
形成により水溶化する方法が知られているが（特
開昭58−148812号公報）、長期継続投与時ピペラ
ジンに起因する副作用が懸念されている。 Sodium salt of ursodeoxycholic acid has PH
9.0 to 11.0, it is 20% or more soluble in water, but this aqueous solution is unstable when heated or stored. To solve this problem, a method has been proposed in which a surfactant and citric acid are added to the sodium salt aqueous solution to stabilize it (Japanese Patent Publication No. 17149/1983), but in this case, the pH during production is adjusted to 9.5 to 11.0. Otherwise, it would not dissolve completely, and due to the high pH, alkaline flex would precipitate from the inner surface of the ampoule glass during storage. In addition, propylene glycol is used as a solvent, and citrate and alkali are added to increase the pH.
7.0 to 8.0 is known (Tokukō 1977)
-37813), this method uses a high concentration of organic solvent such as propylene glycol, which significantly increases the osmotic pressure of the injection solution, which has the drawback of severely restricting its use. A method is known in which ursodeoxycholic acid is made into an ethanolamine salt, a surfactant is added to the aqueous solution, and the salt is completely dissolved at a pH of 9.0 at the time of production (Japanese Patent Publication No. 37814/1983).
Hydrolysis of the surfactant is unavoidable, and the stability of the injection solution decreases due to heat sterilization or aging.
Furthermore, a method is known in which ursodeoxycholic acid is made water-soluble by forming a salt with piperazine (Japanese Patent Application Laid-open No. 148812/1983), but there are concerns about side effects caused by piperazine during long-term continuous administration.
本発明者らはウルソデオキシコール酸はメグル
ミンとの塩形成により水溶化できること、塩化合
物は極めて結晶性が良く、吸湿性が少なく取り扱
いやすいことを見出し本発明を完成した。メグル
ミンについては製剤原料（有機ヨウ素造影剤の溶
解剤）として用いられること、特記されるべき薬
理活性は認められていないことが日本薬局方（第
十改正）に記載されている。 The present inventors completed the present invention by discovering that ursodeoxycholic acid can be made water-soluble by forming a salt with meglumine, and that the salt compound has extremely good crystallinity, has low hygroscopicity, and is easy to handle. The Japanese Pharmacopoeia (10th revision) states that meglumine is used as a pharmaceutical raw material (dissolving agent for organic iodine contrast agents) and that no pharmacological activity that should be noted is recognized.
ウルソデオキシコール酸メグルミンは、例えば
ウルソデオキシコール酸と等モル量のメグルミン
とをエタノール、イソプロパノールなどの有機溶
媒中で加熱して製造することができる。またウル
ソデオキシコール酸メグルミン塩は水溶液中で塩
化合物水溶液として製造することができる。従つ
て、注射剤は塩化合物結晶を水に溶解するか、ま
たは水溶液中にウルソデオキシコール酸と等モル
量のメグルミンとを溶解し、以下注射剤製造の常
法に従つて処理して製造することができ、必要に
応じて等張化剤、PH緩衝剤を添加することができ
る。 Meglumine ursodeoxycholate can be produced, for example, by heating ursodeoxycholic acid and an equimolar amount of meglumine in an organic solvent such as ethanol or isopropanol. Moreover, ursodeoxycholic acid meglumine salt can be produced as an aqueous salt compound solution in an aqueous solution. Therefore, injectables are produced by dissolving salt compound crystals in water, or by dissolving ursodeoxycholic acid and equimolar amounts of meglumine in an aqueous solution, and then proceeding according to the conventional method for producing injectables. If necessary, an isotonizing agent and a PH buffer can be added.
またウルソデオキシコール酸メグルミン塩溶液
を凍結乾燥して用時溶解型の粉末注射剤とするこ
ともできる。 Alternatively, the ursodeoxycholic acid meglumine salt solution can be freeze-dried to form a powder injection that can be dissolved at the time of use.
本発明の注射剤はアンプルに充填したときアル
カリフレツクスを析出しない、有機溶媒を含まな
い、熱・光に対して安定であり貯蔵中に品質低下
しない利点がある。 The injection preparation of the present invention has the advantages of not precipitating alkaline flex when filled into ampoules, containing no organic solvent, being stable against heat and light, and not deteriorating in quality during storage.
実施例 １
イソプロパノール120mlにメグルミン３ｇを懸
濁し、沸とうしない程度に加熱しながら、ウルソ
デオキシコール酸６ｇをイソプロパノール30mlに
溶解した溶液を熱時加えた。この溶液は澄明化し
次いで結晶が析出した。この溶液を冷却後、結晶
を別して乾燥しウルソデオキシコール酸メグル
ミン塩9.0ｇを得た。融点140℃。この塩の赤外線
吸収スペクトルをウルソデオキシコール酸の赤外
線スペクトルと比較すると1720-1cm2のカルボン酸
の吸収が消え、1560-1cm付近にカルボキシレート
の吸収が生じた。Example 1 3 g of meglumine was suspended in 120 ml of isopropanol, and while heating the suspension without boiling, a solution of 6 g of ursodeoxycholic acid dissolved in 30 ml of isopropanol was added while hot. The solution became clear and then crystals precipitated. After cooling this solution, the crystals were separated and dried to obtain 9.0 g of ursodeoxycholic acid meglumine salt. Melting point 140℃. When the infrared absorption spectrum of this salt was compared with the infrared spectrum of ursodeoxycholic acid, the carboxylic acid absorption at 1720 -1 cm 2 disappeared, and the carboxylate absorption appeared at around 1560 -1 cm 2 .
元素分析値 C31H57NO9として
計算値 C63.35％、H9.78％、N2.38％
実測値 C63.47％、H9.70％、N2.45％
以上の塩7.5ｇを水100mlに溶解し塩化ナトリウ
ム0.4ｇを加え、以下常法に従つて注射液を製造
した。この注射液のPHは7.9であつた。Elemental analysis value C 31 H 57 Calculated value as NO 9 C63.35%, H9.78%, N2.38% Actual value C63.47%, H9.70%, N2.45% Add 7.5 g of salt or more to 100 ml of water 0.4 g of sodium chloride was added, and an injection solution was prepared according to a conventional method. The pH of this injection was 7.9.
実施例 ２
メグルミン2.5ｇおよびクエン酸ナトリウム0.6
ｇを水100mlに溶解し撹拌下ウルソデオキシコー
ル酸5.0ｇおよび塩化ナトリウム0.3ｇを加えて溶
解した。この水溶液を無菌過しアンプルに充填
滅菌して注射剤を製造した。この注射剤のPHは
8.0であつた。Example 2 Meglumine 2.5g and sodium citrate 0.6
g was dissolved in 100 ml of water, and while stirring, 5.0 g of ursodeoxycholic acid and 0.3 g of sodium chloride were added and dissolved. This aqueous solution was sterilized and filled into ampoules and sterilized to produce an injection. The pH of this injection is
It was 8.0.
実施例 ３
実施例１の前半部と同様にして製造したウルソ
デオキシコール酸メグルミン塩7.5ｇおよび塩化
ナトリウム0.4ｇを水40mlに溶解し、以下常法に
従つて凍結乾燥して粉末注射剤7.9ｇを得た。Example 3 7.5 g of ursodeoxycholic acid meglumine salt prepared in the same manner as in the first half of Example 1 and 0.4 g of sodium chloride were dissolved in 40 ml of water, and then lyophilized according to a conventional method to obtain 7.9 g of a powder injection. I got it.
実施例 ４
ウルソデオキシコール酸12ｇを水100mlに懸濁
しメグルミン６ｇを加えて、この懸濁液を60℃に
加温すると澄明な溶液となつた。この溶液を常法
により処理して注射剤を製造した。この注射剤の
PHは8.2であつた。Example 4 12 g of ursodeoxycholic acid was suspended in 100 ml of water, 6 g of meglumine was added, and this suspension became a clear solution when heated to 60°C. This solution was processed in a conventional manner to produce an injection. This injection
The pH was 8.2.
Claims (1)
剤。[Claims] 1. Ursodeoxycholic acid meglumine salt. 2 Ursodeoxycholic acid meglumine salt injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1829484A JPS60163897A (en) | 1984-02-06 | 1984-02-06 | Ursodeoxycholic acid meglumine salt and injection containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1829484A JPS60163897A (en) | 1984-02-06 | 1984-02-06 | Ursodeoxycholic acid meglumine salt and injection containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60163897A JPS60163897A (en) | 1985-08-26 |
| JPH0367079B2 true JPH0367079B2 (en) | 1991-10-21 |
Family
ID=11967584
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1829484A Granted JPS60163897A (en) | 1984-02-06 | 1984-02-06 | Ursodeoxycholic acid meglumine salt and injection containing same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60163897A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2387665C2 (en) * | 2004-03-17 | 2010-04-27 | Панакос Фармасьютикалз, Инк. | Pharmaceutical salts of 3-o-(3',3-dimethylsuccinyl) betulinic acid |
| JP2007251281A (en) * | 2006-03-13 | 2007-09-27 | Pioneer Electronic Corp | Speaker |
| CA2945609C (en) * | 2014-07-29 | 2023-05-23 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine-ursodeoxycholic salt, method of preparation and application therof |
-
1984
- 1984-02-06 JP JP1829484A patent/JPS60163897A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60163897A (en) | 1985-08-26 |
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