JPH05246891A - Stable antipancreatitic parenteral solution - Google Patents

Abstract

PURPOSE:To obtain the subject parenteral solution, stable for a long period, capable of performing inspection of insoluble foreign materials and good in operating efficiency, etc., by dissolving an antipancreatitic medicine in a mixture solution of ethanol with propylene glycol and polyethylene glycol. CONSTITUTION:The objective parenteral solution is obtained by dissolving an antipancreatitic medicine such as 6-amidino-2-naphthyl-p-guanidinobenzoate dimethanesulfonate (NM) in a mixture solution of (A) ethanol with (B) propylene glycol and/or (C) polyethylene glycol. The antipancreatitic medicine is preferably dissolved in an amount of 1-5wt.% in the parenteral solution in the case of the NM. The ingredient (A) is preferably contained in an amount of 0.1-20wt.%. Furthermore, the other ingredients are preferably used in the following amounts: 5-8 pts.wt. ingredients (B) and/or (C) based on 1 pt.wt. ingredient (A) and 10-50 pts.wt. ingredient (C) based on 100 pts.wt. ingredient (B).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a stable anti-pancreatitis liquid injection containing a drug for anti-pancreatitis.

[0002]

Various drugs are used as anti-pancreatitis drugs, for example, 6-amidino-2-naphthyl-p-guanidinobenzoate dimethanesulfonate, which is widely used as a therapeutic drug for acute pancreatitis. (Generic name: nafamostat mesylate, abbreviated as NM hereinafter) and ethyl [4- (6-guanidinohexanoyloxy) benzoate] methanesulfonate (generic name: gabexate mesylate, abbreviated as GM hereinafter) It is difficult to keep it stable for a long time as an aqueous solution dissolved in. That is, if these substances are stored in a state of being dissolved in water, they will be hydrolyzed and converted into substances that do not show the original drug effect. Therefore, the commercially available drug product is freeze-dried to remove water to stabilize it, and is distributed as a freeze-dried drug product. It is mixed and diluted to and is infused intravenously. That is, a stable injection solution as a formulation has not been obtained so far.

The above-mentioned freeze-dried preparation is generally used as a liquid drug for a drug having a problem with stability during long-term storage. The stability of lyophilized NM and GM has been solved. However, it has the following problems compared with liquid injections. (1) It is difficult to guarantee reliable sterility. (2) Insoluble foreign matter inspection, which is indispensable for injections, cannot be performed. (3) Since it is dissolved in a small amount of dissolution solution at the time of use and then mixed into a large volume injection solution, the operation is complicated and there are many opportunities for contamination as compared with the liquid injection solution.

[0004]

Therefore, the present invention is based on N
It is an object of the present invention to provide an injection solution which can stably hold anti-pancreatitis drugs such as M and GM.

[0005]

The present invention uses a solvent or stabilizer that is clinically highly safe in order to withstand heat sterilization to ensure sterility and to create a solution that is stable over time. As a result of many studies within the constraint that it must be, ethanol and propylene glycol and /
Or GM or NM in a mixed solution with polyethylene glycol
The present invention has been completed based on the finding that the above object can be achieved by dissolving the above. That is, the present invention provides an anti-pancreatitis injection solution comprising a drug for anti-pancreatitis dissolved in a mixed solution of ethanol and propylene glycol and / or polyethylene glycol.

Here, as polyethylene glycol,
Those having an average molecular weight of about 200 to 400 are preferably used. Ethanol, propylene glycol and polyethylene glycol used in the present invention are substances that have already been used in injections as pharmaceutical additives, and their safety is widely accepted. When GM or NM is dissolved in propylene glycol or polyethylene glycol in a single solvent or in a mixed solution of propylene glycol and polyethylene glycol, the solubility is poor and a practical concentration cannot be obtained. However, by using a small amount of ethanol, the solubility is increased, a practical concentration is obtained, a stable injection solution is obtained against heat sterilization, and a stable injection solution is obtained even after long-term storage.

In the present invention, when the anti-pancreatitis drug is GM, it is dissolved in the above injection solution in an amount of 5 to 35% by weight (hereinafter abbreviated as%), preferably 10 to 25%.
In the case of M, 1 to 5% is preferably dissolved. At this time, it was confirmed that when the amount of ethanol was increased, the amount of GM and NM dissolved increased, and the kinematic viscosity of the solution decreased, but when considering the amount of ethanol that is safe for use as an injection solution, the amount of ethanol was 0.1%. It is better to include ~ 20%. The ratio of ethanol to propylene glycol and / or polyethylene glycol is 1 to 10 parts by weight of ethanol and 2 to 10 of propylene glycol and / or polyethylene glycol.
The amount of propylene glycol and / or polyethylene glycol is preferably 5 to 8 parts by weight with respect to 00 parts by weight, preferably 1 part by weight of ethanol. Furthermore, when a mixed solution of propylene glycol and polyethylene glycol is used, the ratio of the two may be arbitrary, but it is preferable to use 10 to 50 parts by weight of polyethylene glycol to 100 parts by weight of propylene glycol. In addition, it is preferable that the injection solution of the present invention does not contain water as much as possible.

[0008]

According to the present invention, anti-pancreatitis such as 6-amidino-2-naphthyl-p-guanidinobenzoate dimethanesulfonate and ethyl [4- (6-guanidinohexanoyloxy) benzoate] methanesulfonate. A long-term stable injectable solution in which a pharmaceutical drug is dissolved is provided. Therefore, according to the injection solution of the present invention, (1) the insoluble foreign matter test of GM and NM injections, which was impossible by the conventional method, can be performed. (2) GM and N, which were difficult by the conventional method
Assures the sterility of M injections, and (3) improves the operability in preparation before administration and avoids the chance of contamination compared with GM and NM injections prepared by conventional methods. The effect is obtained. Next, the present invention will be described with reference to examples.

[0009]

【Example】

Example 1 Each substance or liquid having the prescription amount shown in Table 1 below was weighed, mixed and dissolved in it, and the liquid amount described in an appropriate amount was used to measure the liquid amount to the total amount column, and the prescription 1 ~ 5 and control products were prepared, filled in 1 ml ampoules and sealed.
Sterilization was performed at 115 ° C for 30 minutes. After sterilization, 40 ° C
Stored at 3 months for stability. The results are shown in Table 2 as a ratio (%) to that before sterilization.

[0010]

[Table 1] Table 1 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Control ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ GM 200mg 200mg 200mg 200mg-100mg NM----10mg -Ethanol 200mg 200mg 200mg 400mg 200mg 200mg Propylene glycol Proper amount Proper amount Proper amount-Proper amount-Polyethylene 500mg--Proper amount 500mg-Glycol 400 polyethylene-500mg----Glycol 300 polyethylene--500mg---Glycol 200 Distilled water---- -Appropriate amount 1 ml 1 ml 1 ml 1 ml 1 ml 1 ml ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━

[0011]

[Table 2] Table 2 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Contrast ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 99.9 99.8 100.0 100.0 99.6 94.5 40 ℃ 1 month storage 99.9 99.7 99.6 99.8 99.4 80.1 〃 2 months save 99.5 99.4 99.6 99.8 99.4 68.5 〃 3 months save 99.3 99.3 99.5 99.8 99.4 59.7 ━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━

Ordinary medicines have an expiration date (expiration date)
Is more than two to three years, and the security cannot be guaranteed unless it is stable for that period. As shown in Table 2, the formulations 1 to 5 were stable to sterilization, and significant decomposition was observed in the control even after storage at 40 ° C., whereas the formulations according to the present invention were completely stable. Was confirmed.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display area A61K 47/32 J 7433-4C

Claims (3)

[Claims] 1. An injectable solution for anti-pancreatitis, which comprises dissolving a drug for anti-pancreatitis in a mixed solution of ethanol and propylene glycol and / or polyethylene glycol. 2. The ethanol content is 0.1 to 20% by weight.
The injection solution according to claim 1, which is 3. The anti-pancreatitis drug is 6-amidino-2-naphthyl-p-guanidinobenzoate dimethanesulfonate or ethyl [4- (6-guanidinohexanoyloxy) benzoate] methanesulfonate. The injection solution according to 1.