JPS5919525B2 - injection - Google Patents

Description

[Detailed description of the invention] The present invention relates to an injection of a benzodiazepine derivative.

Benzodiazepine derivatives are generally poorly soluble in water;
Conventionally, the aqueous solution for injection has been prepared by adding 20 to 7% propylene glycol and/or glycerin and O to 10% sodium benzoate to a benzodiazepine derivative (U.S. Pat. No. 3,123,529).
Diazepam is dissolved in a solution consisting of 30-80% water, 20-70% propylene glycol and/or glycerin, and 0-10% sodium benzoate, and a polyoxyethylene hydrogenated castor oil derivative, polyoxyethylene A diazepam aqueous solution (Japanese Patent Publication No. 48-30373) containing one selected from the group consisting of ethylene castor oil derivatives and stearic acid polyoxyethylene esters, as well as sparingly water-soluble benzodiazepine derivatives, polyoxyethylene sorbitan fatty acid esters, and/or polyoxyethylene sorbitan fatty acid esters. Also known are benzodiazepine derivative injections (Japanese Unexamined Patent Publication No. 126814/1984) comprising polyoxyethylene hydrogenated castor oil derivatives, benzoic acid and/or salicylic acid, benzyl alcohol and/or phenethyl alcohol.

However, since these solutions contain very high concentrations of propylene glycol and sodium benzoate, their osmotic pressure is high, and when intramuscular or intravenous injection, they may cause local muscle effects or hemolysis. , blood vessel disease, etc., and there were considerable problems with the injection formulation.

As a result of extensive research to solve these problems, the present inventors have succeeded in developing an excellent injection that completely dissolves the poorly soluble benzodiazepine derivative and is less irritating when injected. After further research, the present invention was completed.

That is, the present invention provides (a) a benzodiazepine derivative;
(b) polyoxyethylene hydrogenated castor oil derivative and/or
or a polyoxyethylene castor oil derivative, (c) benzyl alcohol and/or phenethyl alcohol, and (d) an aliphatic polycarboxylic acid and/or a salt thereof.

Examples of benzodiazepine derivatives include 8-chloro-6-phenyl-4H-8l-liazolo-[4,3-a
, )(1,4)benzodiazepine, 7-chloro-1,3
-dihydro-1-methyl-5-phenyl-2H-1,4
-benzodiazepin-2-one, 1,3-dihydro-7
-Nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 7-chloro-2-methylamino-5-
Examples include phenyl-3H-1,4-benzodiazepine-4-oxide.

The concentration of the benzodiazepine derivative in the injection solution is usually about 0.01 to 0.5% (by weight)
The amount is preferably about 0.05 to 0.3%.

The polyoxyethylene hydrogenated castor oil derivative used in the present invention has an ethylene oxide average degree of polymerization of about 40 to 1.
about 20, particularly preferably about 50 to 80 derivatives (
Examples, Niracol HCO-30■, Niracol HCO-6
0■, Niracol HCO-30■, etc.; all manufactured by Nikko Chemicals ■).

In addition, as polyoxyethylene castor oil derivatives, derivatives having an average degree of polymerization of about 50 to 80, preferably about 40 (eg, CremophorEL■: Badisc
he Anil ine &5oda FabricA
, G.) etc. are used.

The amount of these surfactants added is approximately 2
It is about 20 parts, particularly preferably about 5 to 15 parts.

The amount of benzyl alcohol and/or phenethyl alcohol added is preferably about 0.5 to 3 parts of the total amount.

Examples of aliphatic polycarboxylic acids include aliphatic oxypolycarboxylic acids (e.g., citric acid, malic acid, tartaric acid, etc.), aliphatic dicarboxylic acids (e.g., succinic acid, maleic acid,
fumaric acid, etc.), among which aliphatic oxypolycarboxylic acids, particularly citric acid, are preferably used.

Salts of such acids include, for example, metal salts (e.g. Nato IJ
salts, potassium salts, etc.).

The amount of aliphatic polycarboxylic acid added is approximately 0.05 to 0.05 of the total amount.
The ratio is about 5, preferably about 0.1 to 2.

The injection of the present invention can be prepared as appropriate according to known preparation methods.

For example, a benzodiazepine derivative that is sparingly soluble in water is dissolved in benzyl alcohol and/or phenethyl alcohol while heating, and a polyoxyethylene hydrogenated castor oil derivative and/or a polyoxyethylene castor oil derivative are separately heated to about 80°C. To this, the benzyl alcohol and/or phenethyl alcohol solution of the benzodiazepine derivative is added dropwise with stirring and mixed to form a homogeneous solution.

Further, a heated aqueous solution containing an aliphatic polycarboxylic acid and/or its salt is gradually added dropwise to this solution while stirring,
When mixed, it becomes a homogeneous aqueous solution.

After cooling this to room temperature, the pH is adjusted with hydrochloric acid or caustic soda, and an appropriate amount of distilled water for injection is added to prepare an injection solution.

After the injection of the present invention, tonicity agents such as common salt and sugars can be added as necessary.

The pH of the injection solution is usually adjusted to about 4.5 to 7.5, and is particularly preferably around the pH of the living body (7.40).

The injectable preparation of the present invention has excellent characteristics such as exhibiting an osmotic pressure almost equal to the osmotic pressure of the living body, little irritation during injection, and extremely low hemolysis, and can be used safely and conveniently. I can do it.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Test Examples below, but the present invention is not limited to these in any way.

Example 1 8-chloro-6-phenyl-4H-8-triazolo-(
4,3-a)(1,4)benzodiazepine (hereinafter referred to as 1)-
(abbreviated as 40TA) 0.1g to benzyl alcohol 1.5
Dissolve by heating in g.

On the other hand, 7.5 g of HCO-50 was melted by heating, and the benzyl alcohol solution of D-40TA was added dropwise thereto, and mixed to form a homogeneous solution.

To this solution, an aqueous solution containing 5 g of sorbitol and 0.1 g of sodium citrate dissolved in advance in 50 ml of distilled water for warming is gradually added with stirring to obtain a clear solution.

Further, the pH was adjusted to 6 with hydrochloric acid or aqueous caustic soda solution, and then distilled water for injection was added to make a total volume of 100 ml.

After filtering this solution with a bacterial filter material, it is filled into a sterile ampoule by aseptic operation, replaced with nitrogen gas, and melt-sealed.

Example 2 0.1 g of D-40TA is dissolved in 1.5 g of benzyl alcohol by heating.

On the other hand, heat 7.5g of Cremophor EL■
The above benzyl alcohol solution of I)-40TA is added dropwise to this to form a homogeneous solution.

Thereafter, in the same manner as in Example 1, 0.1 g of sodium citrate and 5 g of inositol are added to obtain an injection solution with a pH of 6.

Example 3 HCO-30■ of Example 1 and sodium citrate were replaced with HCO-60■8. D-40TA was prepared in the same manner as in Example 1 using Og and 2 g of sodium tartrate.
Obtain injections.

Example 4 0.25 g of diazepam is dissolved in 1.5 g of benzyl alcohol by heating.

On the other hand, 14 g of HCO-30 was melted by heating, and the diazepam benzyl alcohol solution was added thereto and mixed to form a homogeneous solution.

Add 0 salt to this solution in advance in 50 ml of distilled water for warming.
．． An aqueous solution containing 45 g of sodium citrate and 0.1 g of sodium citrate was gradually added with stirring to obtain a clear solution.

Further, add hydrochloric acid or aqueous caustic soda solution to adjust the pH to 6.
Adjust the volume to around 5, and add distilled water for injection to make 100ml.

After filtering this solution with a bacterial filter material, it is filled into an ampoule by aseptic operation, replaced with nitrogen gas, and sealed.

Example 5 A diazepam injection solution was prepared in the same manner as in Example 5 except that 14 g of Cremophor EL and 0.5 g of sodium succinate were used in place of HCO-30 and sodium citrate in Example 4. Create.

Test Example Test Method: An injection solution of the benzodiazepine derivative shown in Table 1 was prepared and tested for each of the following items.

(1) pH: Beckman Model G
Using a mold, pH was measured at room temperature.

(2) Osmotic pressure ratio: Fiske osmometer G66
Type (F1ske As5ociates, Inc.
, ,Uxbridgc.

Osmotic pressure was measured by the freezing point depression method using Mass., U, S, A).

The value obtained by dividing this value by the osmotic pressure of 0.9 saline was defined as the osmotic pressure ratio.

(3) Local effects: 1 ml of each injection solution was administered to the vastus lateralis muscle of a domestic rabbit, and after 24 hours, the rabbit was sacrificed, the vastus lateralis muscle was removed, the muscle was incised, and the degree of damage was observed with the naked eye. and will be judged by the following score [S.

5hintani et, al,, Toxicolog
y and Applied Pharmacolog
y 11 , 293-301 (1967)).

(4) Hemolysis: 0.1 ml of titrate human blood was added to 10 ml of each injection solution, shaken at 37°C, and the time taken for hemolysis to begin was observed.

(5) Pain test: When 0.2 ml of each of formulations A and B was subcutaneously injected into rabbits, their behavior was observed and the presence or absence of pain was estimated.

Its strength is expressed by a symbol from 1 to 2.

-: No pain response at all ±: Almost no pain response +: Very weak pain response +1-: Pain response +1+:
As shown in Table 3, Formulation B was significantly improved as an injection liquid formulation.

Claims (1)

[Claims] 1 (a) benzodiazepine derivatives, (b) polyoxyethylene hydrogenated castor oil derivatives and/or polyoxyethylene castor oil derivatives, (c) benzyl alcohol and/or phenethyl alcohol, and (d) aliphatic polycarboxylic acids and/or their An injection containing salt.