JPS60163897A - Ursodeoxycholic acid meglumine salt and injection containing same - Google Patents

Abstract

NEW MATERIAL:Ursodeoxycholic acid meglumine salt. USE:Cholagogue and lithotriptic agent for injection. It does not precipitate alkali reflex when filled in an ampule, and is stable to light and heat and preservable without degradation. PREPARATION:For example, ursodeoxycholic acid and equimolar amount of meglumine are heated in an organic solvent such as ethanol, and the resultant solution is cooled to precipitate the objective salt in the form of crystal.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ursodeoxycholic acid meglumine salt and its injection solution.

Ursodeoxycholic acid is a drug that is widely used as a choleretic agent and gallstone dissolving agent, but it is hardly soluble in water and must be made into an aqueous solution.

In particular, it has been studied to be used as an injection solution.

Sodium salt of ursodeoxycholic acid starts from P1490
11.0 and 20% or more": Dissolves in water, but this aqueous solution is unstable against heating or storage. In order to solve this problem, a method has been proposed in which a surfactant and citric acid are added to the IJum salt aqueous solution to stabilize it (Japanese Patent Publication No. 35-17149), but in this case, P11 at the time of production is
．． If it is not adjusted to 5 to 11.0, it will not dissolve completely and P
Due to the high H content, there was a drawback that alkaline flex was precipitated from the inner surface of the ampoule glass during storage. A known method is to use propylene glycol as a solvent and adjust the pH to 7.0 to 80 by adding citrate and an alkali (Japanese Patent Publication No. 37813/1973); Because the organic solvent is used at a high concentration, the osmotic pressure of the injection solution increases significantly.

The drawback is that there are significant restrictions on its use.

There is a known method in which ursodeoxycholic acid is made into an ethanolamine salt, a surfactant is added to the aqueous solution, and the solution is completely dissolved at p+-(90%) during production (Japanese Patent Publication No. 48-37).
No. 814), hydrolysis of the surfactant is unavoidable,
The stability of the injection solution decreases due to heat sterilization treatment or aging. In addition, a method is known in which ursodeoxycholic acid is made water-soluble by forming a salt with piperazine (Japanese Patent Laid-Open No. 1983-1995).
148812), there are concerns about side effects caused by piperazine during long-term continuous administration.

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 (Saiko Revised Edition) states that meglumine is used as a pharmaceutical raw material (dissolving agent for organic iodine contrast agents) and that no pharmacological activity to be noted is recognized.

Meglumine ursodeoxycholate can be produced, for example, by heating an equimolar amount of meglumine to ursodeoxycholic acid in an organic solvent such as ethanol or isopropanol. The ursodeoxycholic acid meglumine salt can be prepared as an aqueous solution of the salt compound in an aqueous solution. Therefore, injectables can be manufactured by dissolving salt compound crystals in water or by dissolving meglumine in an amount equivalent to ursodeoxycholic acid in a strained aqueous solution, and then proceeding according to the conventional method for manufacturing injectables. It is possible to add an isotonizing agent and a PH softening agent if necessary.

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.

The injection preparation of the present invention has the advantages of not precipitating alkaline flex when filled into an ampoule, containing no organic solvent, being stable against heat and light, and not deteriorating in quality during storage.

Example 1 Meglumine 37 was suspended in 120 ml of Improper Tool, and while heating the suspension without boiling, a solution in which ursodeoxycholic acid 67 was dissolved in 30 ml of Improper Tool was added while hot. The solution clarified - then crystals precipitated. After cooling this solution.

The crystals were dried separately to obtain ursodeoxycholic acid meglumine salt 907. Melting point 1.40tZ'. When the infrared absorption spectrum of this salt was compared with the infrared spectrum of ursodeoxycholic acid, the carboxylic acid absorption at 1720-''(ffl) disappeared and the carboxylate absorption appeared around 1.560 am.

Elemental analysis value C3, HI, 7N Calculated value as O9 C
63, 35 section, T-19, 78%, N2.38% Actual value C63, 47 section, IT 9.70%, N 2.45
% The above salt 757 was dissolved in 100 ml of water, sodium chloride 04f was added, and an injection solution was prepared according to a conventional method. The pH of this injection solution was 79.

Example 2 Meglumine 251 and sodium citrate 067 were dissolved in 100 ml of water, and ursodeoxycholic acid 5 was added under stirring.
0 g and 0.39 sodium chloride were added and dissolved.

This aqueous solution was filtered aseptically and filled into ampoules and sterilized to produce an injection.The PII of this injection was 80.

Example 3 Ursodeoxycholic acid meglumine salt 7.5y produced in the same manner as in the first half of Example 2 and chloride) IJ
Um-042 was dissolved in 40 ml of water and freeze-dried according to a conventional method to obtain powder injection 797.

Example 4 Ursodeoxycholic acid 127 was suspended in 100 ml of water, meglumine 67 was added, and the suspension was heated to 600 ml to become a clear solution. This solution was processed in a conventional manner to produce an injection. The pH of this injection was 82.

Patent applicant: Tokyo Tanabe Pharmaceutical Co., Ltd. Agent Hisataka Masanobu outside - first name Supplementary Procedures (Method) 1980 5J] 16th Mr. Kazuo Wakasugi, Commissioner of the Patent Office ], Incident display Special request No. 18, 1980, 294 2. Name of the invention Ursodeoxycholic acid meglumine salt and its injection 3. Person who makes corrections Relationship to the incident: Patent applicant Tokyo Tanabe Pharmaceutical Co., Ltd. 4 agents

Claims (1)

[Claims] ■ Ursodeoxycholic acid meglumine salt. 2 Ursodeoxycholic acid meglumine salt injection.