JP4557098B2 - Stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and method for producing the same - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation and a method for producing the same.
[0002]
[Prior art]
6-Amidino-2-naphthyl 4-guanidinobenzoate acid addition salt has a proteolytic enzyme inhibitory action, blood coagulation / fibrinolytic system (thrombin, XIIa, Xa, VIIa, plasmin), kallikrein-kinin system (kallikrein), It is known to have a potent inhibitory action on the complement system (C _1r , C _1s , B, D) and pancreatic enzymes (trypsin, pancreatic kallikrein).
[0003]
The inhibition of thrombin does not depend on antithrombin III, the blood coagulation time is strongly prolonged, and it has a strong inhibitory effect on platelet aggregation. From this, strong usefulness against generalized intravascular blood coagulation (DIC) is recognized.
[0004]
In addition, a strong inhibitory action on both trypsin and α ₂ -macroglobulin-bound trypsin and an inhibitory action on phospholipase A ₂ have been confirmed to be highly useful for improving acute symptoms of pancreatitis.
[0005]
Since 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt is unstable in an aqueous solution, it is used as a preparation which is dissolved at the time of use.
[0006]
[Problems to be solved by the invention]
The object of the present invention is to provide 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt which can be stably stored for a long time after dissolution of 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt which is unstable in aqueous solution It is to provide a preparation and a production method thereof.
[0007]
[Means for Solving the Problems]
As a result of extensive research to solve the above problems, stable lyophilization is achieved by dissolving succinic acid in water together with 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt and freeze-drying this aqueous solution. It was found that a formulation was obtained.
[0008]
In the present invention, the 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt is an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like with respect to 1 mol of 6-amidino-2-naphthyl 4-guanidinobenzoate, or , Acetic acid, lactic acid, citric acid, methanesulfonic acid, 4-toluenesulfonic acid, succinic acid, fumaric acid, maleic acid, and other organic acids that can be used as pharmaceuticals are used.
[0009]
In the present invention, such 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt and succinic acid are added at a weight ratio of 15 to 5: 1, more preferably 10: 1, and frozen. Dry.
[0010]
In this lyophilization, one or more of D-mannitol, lactose and sucrose are added in an amount of 1 to 3 times, more preferably about 2 times the amount of 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt. It is desirable to blend to the extent.
[0011]
These may be dissolved in an appropriate amount of water, dispensed into glass vials, and lyophilized. At this time, the amount of water used is usually about 20 to 200 times the weight of 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt.
[0012]
Freeze-drying is performed by a conventional method. As lyophilization conditions, for example, preliminary freezing; −50 to −5 ° C. for 5 to 20 hours, then primary drying; −10 ° C. to 10 ° C. for 20 to 50 hours, secondary drying; It is desirable to carry out in order of ~ 30 hours.
Specifically, after preliminary freezing at −45 ° C. for 8 hours, primary drying may be performed at 0 ° C. for 40 hours, and secondary drying may be performed at 25 ° C. for about 15 hours.
[0013]
Since lyophilization has a long time as described above, 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt which is unstable in an aqueous solution is freeze-dried by the method of the present invention. Degradation can be minimized and a stable formulation can be provided. Furthermore, the 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt preparation produced according to the present invention can be kept stable for more than 24 hours after dissolution at the time of use.
[0014]
Next, the present invention will be described in more detail with reference to examples.
[0015]
【Example】
6-amidino-2-naphthyl 4-guanidino benzoate dimethyl chest Gandolfo sulfonate _{(C 19 H 17 N 5 O} 2 · 2CH 3 SO 3 H) 20g, a D- mannitol 40g and succinic acid 2g was dissolved in water, and accurately 2L did. This solution is filtered through a 0.45 μm filter, dispensed in 1 mL portions into glass vials, and then freeze-dried (preliminary freezing at −45 ° C. for 8 hours, followed by primary drying at 0 ° C. for 40 hours, secondary drying) 15 hours at 25 ° C.). After completion, it was stoppered and tightened with an aluminum cap.
[0016]
The 6-amidino-2-naphthyl 4-guanidinobenzoate-dimethanesulfonate freeze-dried preparation thus prepared was dissolved in 10 mL of water, and 2 μL of this solution was accurately taken, and subjected to liquid chromatography under the following conditions: The peak area of 6-amidino-2-naphthyl 4-guanidinobenzoate was measured to determine the residual ratio of 6-amidino-2-naphthyl 4-guanidinobenzoate.
[0017]
The operating conditions of the liquid chromatography method are shown below.
Detector: UV absorptiometer (measurement wavelength: 261 nm)
Column: YMC-Pack ODS-AM AM-303
(5 μm, 4.6 mm × 250 mm, manufactured by YMC Corporation)
Column temperature: constant temperature around 35 ° C. Mobile phase: diluted phosphoric acid (1 → 1000) / acetonitrile mixture (9: 1)
Injection volume: 2 μL
Flow rate: 1 mL per minute
[0018]
As a result, 99.90% immediately after dissolution, 99.85% after 1 hour, 99.86% after 2 hours, and 99.62% after 24 hours, it was stable.

Claims (2)

To 6-amidino-2-naphthyl 4-guanidino benzoate _{(C 19 H 17 N 5 O} 2) acid addition salts 15-5 parts, 1 part of succinic acid, D- mannitol, one or more of lactose and white sugar A stable 6-amidino-2-naphthyl obtained by dissolving 35 to 5 parts of the above in 20 to 200 times the amount of water and freeze-drying, and hardly decomposes for 24 hours after dissolution 4-Guanidinobenzoate acid addition salt lyophilized formulation. To 15 to 5 parts of 6-amidino-2-naphthyl 4-guanidino benzoate acid addition salt, 1 part of succinic acid, D- mannitol, one or more of 35-5 parts of lactose and white sugar, from 20 to 200 A stable 6-amidino-2-naphthyl 4-guanidinobenzoate acid addition salt freeze-dried preparation characterized by dissolving in double volume of water and freeze-drying, with almost no degradation over 24 hours after dissolution Production method.