JPS58201712A - Oil emulsion - Google Patents

Abstract

PURPOSE:An oil emulsion that contains an indolacetic ester, thus showing anti- inflammatory and antipyretic effect with a long duration, high safety and reduced side-effects. CONSTITUTION:An indolacetic ester of the formula (R is 1-18C alkyl, -CH2 COOR) is dissolved in a base for the oil emulsion and solution is combined with water, then homogenized to give the objective oil emulsion. The compound of the formula has high anti-inflammatory and analgesic activity, being widely used clinically. Since the compound is weaker in its activities than the compound of the formula where R is H (indomethacine) or that where R is -CH2COOH (acetmethacin), it has not been used, however, its use in the form of oil emulsion shows the same level of the pharmaceutical effect as of indolacetic acids, moreover, causes no dangerous side-effects such as troubles in digestive tracts, injection shocks or allergy.

Description

DETAILED DESCRIPTION OF THE INVENTION The novel fat emulsion according to the present invention, more specifically, the general formula (1)
A fat emulsion containing indole acetate esters represented by: Regarding.

(1) Compounds in which R is a hydrogen atom or -afI, cooH (hereinafter these are referred to as "indole compounds")
) have excellent anti-inflammatory and analgesic effects and are widely used in clinical practice, but indole acetate esters represented by formula (1) are said to have weak effects and are not used.

Indo-alcotic acids are available in the form of free carboxylic acids in the form of oral preparations or suppositories, or in the form of alkali salts in the form of injections, but oral preparations and suppositories often cause serious gastrointestinal disorders. However, injections also have the disadvantage of causing side effects such as shock and allergies.

Therefore, it is especially important for patients who have difficulty receiving oral administration, such as cancer patients! Pain/
Patients with no post-operative pain etc. wanted an injection with long-lasting effects and no side effects such as those mentioned above.

Under such circumstances, the present inventor conducted intensive research and found that, surprisingly, the effect was thought to be weak (1).
It was discovered that when indole acetic acid esters of the formula ) are administered in the form of a fat emulsion, pharmacological effects equivalent to those of indole acetic acids can be obtained, there are few side effects, the safety is high, and the duration of action is long, and the present invention has been achieved. completed.

That is, the present invention provides indole acetic acid esters (1)
3. The fat emulsion of the present invention is a conventional oil-in-water emulsion in which indole acetic acid esters are dissolved in a fat emulsion base, and water is added to the solution and homogenized. Manufactured using the manufacturing method.

Indole acetates are known as indomethacin (
R=H) or acemetacin t, R=-qH,, O, O
It is produced by esterifying OH, ) and the corresponding alcohol using a conventional method.

Examples include fat emulsion bases and pharmaceutically acceptable glues/lipids such as phosphatidixerin and sphingoemylin that dissolve indole acetate esters.

Furthermore, emulsification aids such as fatty acids, albumin, dextran, nonionic surfactants, and gelatin may be added to the emulsion, if necessary.

The content of indole acetate in the fat emulsion is:
Although it can be increased or decreased as appropriate depending on the form and purpose of the emulsion, it is generally preferable that the emulsion contains 01)01 to 104-weight φ.

Although the fat emulsion of the present invention can be administered in various dosage forms, intravenous administration is particularly preferred.

The dosage varies depending on the route of administration, dosage form, and symptoms, but it can be administered as an emulsion up to 1,000,114 doses/dose.

Next, the results of testing the pharmacological effects of the fat emulsion of the present invention will be shown.

Experimental example 1. (Anti-inflammatory effect) Using male Wistar rats (6 rats per group), 0.05-ml of a solution of 1 thicalagenin dissolved in physiological saline was subcutaneously administered to the right hind paw at 1 fK to induce paw edema. Two hours after administration of carrageenan, the drug to be saponified (1 g/K as indomethacin) was administered.
p) was administered through the tail vein, and thereafter, the constant volume was measured over time. As test systems, those manufactured in Example 1 (drug of the present invention 1) and Example 8 (drug of the present invention 2) were used, and as a comparative drug, an aqueous solution of indomethacin sodium salt was used.

The results are as shown in FIG. 1, and the fat emulsion of the present invention exhibited a clear anti-inflammatory effect, and its effect tended to be seven times stronger than that of the comparative drugs.

This indicates that the compound of formula (1) administered by the fat emulsion of the present invention has good local concentration at the site of inflammation.

Experimental example 2. (Antipyretic effect) Using the test system (indomethacin and l-
So 0.5 m97? ) It was administered through the tail vein. Rectal temperature was measured until 4 hours after administration, and the difference in body temperature from before administration was calculated.

The same system as in Experimental Example 1 was used as the test system.

The results are shown in FIG. 2, and the drug of the present invention showed an effect equal to or higher than that of the comparative drug.

Examples will be described below.

Example 1 Refined soybean oil 100. Of purified egg yolk phospholipid 12, Of
, indomesacin cetyl ester (melting point 47-49°C)
2. Add Of and dissolve by heating at 50 to 80°C. Furthermore, the purified egg yolk phospholipid is uniformly dispersed using a homogenizer. Next, about 70011B of distilled water is taken, and glycerin 25f is dissolved therein by heating to uniformly dissolve it. The indomesacin cetyl ester and purified soybean oil containing 7-purified egg yolk phospholipid are placed in an aqueous glycerin solution, and the entire amount is poured into an IE with distilled water, followed by rough emulsification.

After rough emulsification, use a high-pressure injection emulsifier, and the initial stage pressure is 120KP/
♂, emulsification under a total pressure of 560 KP/;- about 1 to 1
．． Do it for 5 hours. During emulsification, maintain the liquid temperature at 65-75°C.

, whereby a fat emulsion containing indomesacin cetyl ester was obtained. This emulsion is of uniform quality,
The average particle diameter was 0.2 to 0.4μ, and no particles larger than 1μ were contained.

Example 2 0.51 oleic acid and 0.5f phosphatidic acid,
A fat emulsion containing an ester of indomethacin cetyl ester having analgesic and anti-inflammatory activity was obtained by carrying out the same treatment as in Example 1 except that purified egg yolk lecithin and purified soybean oil containing indomethacin cetyl ester were added.

Example 3 Cholesterol 0 was used instead of phosphatidic acid in Example 2.
, 5f was treated in a similar manner to obtain a fat emulsion containing indomesacin cetyl ester having analgesic and anti-inflammatory activity.

　　　.

Example 4 Indomethacin stearyl ester (melting point 56-58
A fat emulsion having analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 1, except for adding .

Example 5 A fat emulsion having analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 2, except that indomethacin myristyl ester was added instead of indomethacin cetyl ester.

Example 6 Indomethacin cetyl ester (melting point 92-94°C) was used instead of indomesacin cetyl ester in Example 3.
A fat emulsion having analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 3 except for adding .

Example 7 A fat emulsion having analgesic and anti-inflammatory activity was obtained in the same manner as in Example 1 except that indomethacin butyl ester 'lr was added instead of indomethacin cetyl ester.

Example 8 A fat emulsion having analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 1 except that K acemetacin ethyl ester was added instead of indomethacin cetyl ester O.

Example 9 A fat emulsion having analgesic and anti-inflammatory activity was obtained by carrying out the same operation as in Example 2 except that acemethacin cetyl ester (melting point 68-69°C) was added instead of indomesacin cetyl ester. Ta.

[Brief explanation of the drawing]

11- Fig. 1 shows the anti-inflammatory effect when the fat emulsion of the present invention was administered intravenously to rats, and Fig. 2 shows the antipyretic effect when the same fat emulsion was intravenously administered to rats. Applicant: Midori Juji Co., Ltd.: 1, ++1 L+,,',,,,,',',,1 12- 1 ~ cc! Enemy Tatsumi 0 Roro

Claims (1)

[Claims] 1. General formula [wherein R is a C1 to Ova linear or branched alkyl group or a group -OH,0OOR (R has the above meaning)
] A fat emulsion containing an indole acetate represented by the following.