JPS60208911A - Diazepam preparation for rectal infusion - Google Patents

Abstract

PURPOSE:To prepare the titled drug preparation having excellent transrectal absorption and transferability to the brain, and low toxicity, by adding a compound selected from aleic acid, calcium chloride, EDTA and glycine as an assistant to promote the transrectal absorption. CONSTITUTION:The objective diazepam preparation for rectal infusion can be prepared by mixing diazepam with one or more compounds selected from maleic acid, calcium chloride, EDTA and glycine as an assistant to promote the transrectal absorption. The agent is administered in the form of suppository, rectal infusion, etc., and the infusion is preferable because the control of the dose can be carried out easily. The base of the infusion is e.g. propylene glycol, etc., and above all, methylacetamide, benzoic acid, etc. are especially preferable because of its low stimmulation to the rectum and anus, etc. The amount of the absorption assistant is 0.1-5w/v% of the preparation. Dose: 20-30mg for adult and 5-10mg for child by rectal infusion.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a diazepam enema solution that has excellent rectal absorption and transferability to the brain and has low eta-activity.

Diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-
2-one) has traditionally been used to treat spasticity because it has a strong anti-N curvature effect in addition to its sedative and muscle relaxing effects. Diazepam is usually used as an oral preparation or an injection solution, but oral preparations are slowly absorbed and require time to take effect. Among injection solutions, when administered intravenously, it is necessary to secure an intravenous route and administer at a slow rate, while when administered intramuscularly, it causes irritation such as pain, and administration to children or younger is prohibited.

In order to avoid side effects caused by injection, half-open administration is also proposed. However, even when the drug is half-opened, absorption is faster than that of the oral preparation, but it is still not satisfactory, and the amount of administration is difficult to control.

In order to avoid such side effects caused by injection, a rectally administered formulation has been proposed, but although its absorption is faster than that of an orally administered formulation, it is still unsatisfactory.

Under these circumstances, the present inventors conducted various research and found that diazepam was treated with maleic acid and calcium chloride (C).
When administered rectally together with aCI2), EDT A, or glycine, the rectal absorption of diazepam is promoted, the blood concentration of diazepam increases rapidly, and the drug has good transitivity to the brain, which is the active organ. They found that there is little accumulation in °C, and after further research, they completed the present invention.

That is, the present invention provides at least diazepam and diazepam rectal absorption promoting agent, which is at least 1 selected from maleic acid, calcium chloride, E D "l" A, and glycine.
The present invention relates to a diazepam rectal administration preparation characterized by containing one or more species.

The preparation of the present invention may be in a known dosage form, such as a halved form or an enema solution, and an enema solution is more suitable because the dosage can be easily adjusted.

As bases for these preparations, conventionally known bases may be used.

In particular, bases (dissolving agents) for enema solutions include propylene glycol, polyethylene glycol, methylacetamide, methylpyrrolidone, benzoic acid and its salts, glycyrrhizinate, hippurate, nicotinic acid and its salts, and nicotinic acid amide. , N-methylnicotinamide, and the like. Among these, particularly preferred are methylacetamide, methylpyrrolidone, benzoic acid and its salts (e.g., alkali metal salts such as sodium salt, etc.), glycyrrhizinate (e.g., alkali metal salts such as dipotassium salt, etc.), and hippuric acid. salts (e.g., alkali metal salts such as sodium salts), nicotinic acid and its salts (e.g., alkali metal salts such as sodium salts), nicotinamide, N-methylnicotinamide, etc. This is particularly preferred since it has the advantage of being less irritating.

Note Il! In the liquid, it is preferable to further include ethyl alcohol, Hensyl alcohol, etc. as a solubilizing agent.

Absorption aids are commonly used in the formulation of the present invention, with a concentration of π0.1 to 5w/V
%, ★Y preferably 0.2 to 2 W/v%.

In the case of the above amount, there is little irritation to the rectum and anus, and the effect of promoting absorption is also excellent.

The solubilizer usually has a concentration of 10 to 60 W/V%, preferably 10 to 60 W/V%.
It is blended at 55 w/v%.

The solubilizing agent has a content of 1.5 to 20 W/V%, preferably 7 to 20 W/V%.
It is blended at 17 w/v%. If the product is used beyond this point, the irritation to the rectal area will become stronger.

Other ingredients included in the enema include water, glycerin, and the like.

The water content is usually 20 to 65 w/v%, preferably 3
It is 5 to 65 w/v%.

The enema solution of the present invention is 1st for febrile diseases in children! It is used for the treatment of convulsions such as Ichi-Xil condition and for the sedation of children in the pediatric Yuri region, by injecting 20 to 30 mg/person for adults and 5 to 10 mg/person for children through the anus.

Examples of the present invention are shown below.

Example 1 5 g of diazepam was dissolved in a mixed solution of 501 ethanol I and 15 ml of Hensyl alcohol, and 275 g of N-methylnicotinamide, 12 g of malein and water were added (to make 1 p). Fill a container to make a preparation containing 10 mg of diazepam.

Example 2 5 g of diazepam was dissolved in a mixed solution of 150 nL of ethanol + 151 nL of Hensyl alcohol, and 300 g of propylene glycol, 100 g of N-methylnicotinamide, 2 g of maleic acid, and water were added to make 11. Add this solution to 21
Fill each into an enema container to prepare a preparation containing 10 mg of diazepam.

Example 3 5 g of diazepam was dissolved in a mixed solution of 150 ml of ethanol and 15 ml of Hensyl alcohol, and 460 g of propylene glycol, 16 g of N-methylnicotinamide, 11.5 g of malein ff and water were added to make up to 1 liter. Fill 2 ml of this solution into an enema container and add 10 ml of diazepam.
g-containing preparation.

Example 4 5 g of diazepam was dissolved in a mixed solution of 150 ml of ethanol and 15 ml of Hensyl alcohol, and 138 g of N-methylnicotinamide, 110 g of nicotine r, 8 g of maleic acid and water were added to make 1ffi.

Fill 2 ml of this solution into an enema container to prepare a preparation containing 10 mg of diazepam.

Example 5 5 g of diazepam was dissolved in a mixed solution of 150 ml of ethanol and 15 ml of Hensyl alcohol, and 311 ml of N-methylnicotinic acid and 138 strium benzoate were dissolved.
g, malein I'& 4 g and water were added to make °ζIl.

Fill 2 ml of this solution into an enema container to prepare a preparation containing 10 mg of diazepam.

Example 6 5 g of diazepam was dissolved in a mixed solution of 150 ml of tanol and 15 ml of hensyl alcohol, and 138 g of N-methylnicotinamide, 138 g of nicotinic acid amide, 4 g of maleic Fn and water were added to prepare I7! Closed. This /8
Fill 2 ml of the solution into an enema container and add 10 ml of diazepam.
g-containing preparation.

Example 7 5 g of diazepam was dissolved in a mixed solution of 11 ml of ethanol and 15 ml of Hensyl alcohol, and 138 g of dipotassium glycyrrhizinate, 2 g of maleic acid and 2 g of water were added to make up to 1 liter. This solution is filled into two containers for enema to prepare a preparation containing 10 mg of diazepam.

Example 8 5 g of diazepam was dissolved in a mixed solution of 150 ml of ethanol and 151 ml of Hensyl alcohol, and 275 g of N-methylnicotinamide, 220 g of CaCl and water were added.
It was set as p. Fill 2 ml of this solution into an enema container,
The preparation contains 10 qg of diazepam.

Example 9 5 g of diazepam was dissolved in a mixed solution of 50 ml of ethanol and 15 ml of benzyl alcohol, and 2 g of sodium hippurate was dissolved.
70g, polyethylene glycol 4000275g, C
220 g of aCl and water were added to make up to 1 liter. Fill 2 ml of this solution into an enema container to prepare a preparation containing 10 mg of diazepam.

Example IO 5 g of diazepam was dissolved in a mixed solution of 100 ml of ethanol and 15 ml of benzyl alcohol, and 275 g of propylene glycol, 135 g of sodium benzoate, El)
Add TA-2 sodium Ig, 5g of glycine and water and lj! And so. Fill 2 ml of this solution into an enema container to prepare a preparation containing diazepam IO+B.

Example 11 5 g of diazepam was dissolved in a mixed/8 solution of 150 ml of ethanol and 15 ml of benzyl alcohol, and 550 g of methylpyrrolidone, 18 g of maleine ff, and water were added to ζI.
It was set as e. Fill 2 ml of this solution into an enema container,
One formulation containing diazepam 10IllR.

Comparative example 1 A formulation in which maleic acid was removed from the formulation of Example 1.

Comparative example 2 (commercially available injection) diazepam + 1.5 W/V%, propylene glycol 4
0%, sodium benzoate and benzoic acid 5w/V%,
Ethylua! Renyl 1()%, benzyl alcohol 1
．． Water containing 5%/8/& Comparative Example 3 (11 intestinal fluids in clinical use) Diazepam 0
．． 5w/v%, Brikotsu "1-le" 55w/v%, ethanol 9w/v%, benzyl alcohol 1.5w/v%
Experimental Example of Aqueous Solution Containing V% An experiment was conducted to investigate the transfer of diazepam into the brain after enema of a diazepam-containing preparation. As diazepam, 3H
- Diazepam (radioactivity 4 μc/mg) was used, and each preparation was obtained in the same manner as in each Example 1-11. Wistar rats (male) were used as experimental animals, and 0.2 ml of each preparation was injected into the rat's intestine, and 3H in the brain was measured over time using a scintillation counter to examine the movement of diazepam into the brain. The results are shown in Figure 1. As a result, the present formulation (×−×)
It was demonstrated that the drug was rapidly transferred into the brain. Although FIG. 1 shows only Example 1 among the formulations of the present invention, other formulations of the present invention also showed similar results. In addition, as a comparative example, the formulation of Example 1 except that maleic acid was removed (Comparative Example 1.xx-x),
A commercially available injection solution (Comparative Example 2.--) and a clinically used enema solution (Comparative Example 3.0-0) were used.

As is clear from the results shown in Figure 1, the preparation of the present invention has excellent rectal absorption and brain transferability, and after the onset of its effect, it is rapidly excreted without accumulating in the brain, and is immediately absorbed into the brain. is returned to a positive state.

4. Brief explanation of the drawings ＾ Figure 1 is a graph showing the superiority of the formulation of the present invention. Goharuma-J2 3geε (City LiJE Printing: (Spontaneous) Showa 6
May 10, 01, Indication of the case 1982 Patent Application No. 060060 2 Name of the invention Diacepam Rectal Administration Preparation 3 Relationship with the Ministry case making the amendment Patent applicant name Midori Juji Co., Ltd. 4, Agent ■541 Address: 4-53-3 New Life Hirano-cho, Higashi-ku, Osaka 406 lFt ((16) 227-1156 Specification 1 Detailed Description of the Invention'' 6, Contents of amendment

Claims (1)

[Scope of Claims] 11) At least diazepam and diazepam rectal absorption 4% promoting agent ζ, maleic acid, calcium chloride,
E l) Diazepam rectal administration preparation characterized by containing 144 (or two or more) selected from i'Δ and glycine. (2) Diazepam solubilizing agent: C, methylacetamide, methylpyrrolidone, benzoic acid and its salt, glycyrrhizinate, hippurate, nicotinic acid and its salt, nicotinic acid amine), N-methylnicotinic acid '1 amide, or 24117 to 42. Diazepam rectal administration preparation according to scope item (1).