JPS5815912A - Antiphlogistic and analgesic agent - Google Patents

Abstract

PURPOSE:To prepare a useful antiphlogistic and analgesic agent having suppressed side effects such as gastrointestinal disorder, without lowering the main effect of a non-steroid antiphlogistic and analgesic substance, by compounding a non-steroid antiphlogistic and analgesic substance and a 2,3-butanediol diester derivative as active components. CONSTITUTION:A non-steroid antiphlogistic and analgesic substance (e.g. indomethacin, aspirin, phenylbutazone, etc.) and a 2,3-butanediol diester derivative of formulaI(R1 and R2 are alkyl, alkenyl or group of formula II; R3 is H, alkyl, or cyano; R4 is phenyl, etc.) are used as active components, and mixed properly with a diluent such as starch, a binder such as sodium carboxymethylcellulose, etc. The amount of butanediol diester is preferably >=0.1pt., especially 1-20pts. per 1pt. of the non-steroid antiphlogistic and analgesic substance.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an anti-inflammatory and analgesic agent with low action, which is a combination of a non-steroidal anti-inflammatory analgesic agent and a 2.6-butanediol diester derivative.

Conventionally, indomethacin, aspirin, phenylbutadine, etc. have been used as non-steroidal anti-inflammatory and analgesic substances for pain relief, toothache, l.
! It is widely used to treat pain, muscle pain, rheumatic diseases, etc.

However, these substances have the potential to cause gastrointestinal disorders associated with the development of ulcers, so they may cause gastric congestion, bleeding, etc. not only when long-term administration is required, such as in the treatment of rheumatic diseases, but even when administered for short periods of time. Therefore, the present inventors conducted extensive research into methods for reducing the side effects of nonsteroidal anti-inflammatory and analgesic substances, and found that The formula (1
), τH3 H3 [wherein R1 and R2 are the same or different, alkyl is a hydrogen atom, an alkyl group, or a cyano group, and R4 is a phenyl group, a halogen atom, an alkyl group, an alkoxy group, or two or more acyloxy groups. 2,6-butanediol diester derivative (hereinafter simply referred to as ``butanediol diester'') represented by The present invention was completed based on the discovery that only the occurrence of side effects such as gastrointestinal disorders can be significantly suppressed without attenuating the main effect.

That is, the present invention provides an anti-inflammatory analgesic agent containing a non-steroidal anti-inflammatory analgesic substance and a butanediol diester represented by the above formula (1).

The nonsteroidal anti-inflammatory analgesic substances that are the medicinal ingredients of the anti-inflammatory analgesic combination of the present invention include indomethacin, aspirin, phenylbutadine, salicylamide, etendemide,
oxyphenbutacin, ketophenylbutacin, sulfinpyrazone, mefenamic acid, flufenamic acid, diclozenaf sodium, methiazine acid, nazoloxene, tiaramide, pumadizone, benzydamine hydrochloride, ibufenac, ibnolofen, zocolome, mepirizole, adesolopazone, tinoridine hydrochloride, Examples include clo7ezone, noropenecid, ketonorophen, and the like. this house,
In particular, indomethacin, aspirin, phenylbutazo/1oxyphencytacin, ketophenylcitacin, mefenamic acid, flufenamic acid, diclozenaf sodium, nazoloxene, ibufenac, ibuprofen, clo7ezone, ketonorophen, etc., which cause gastrointestinal disorders, etc. It is advantageous to incorporate butanediol diester into the anti-inflammatory and analgesic agent of the present invention because side effects such as gastrointestinal disorders are significantly reduced.

In addition, butanediol diester (1
) is a known compound or a compound easily obtained by a known general esterification method. For example, according to the following reaction formula, carboxylic acid chloride (1) is mixed with a deoxidizing agent in a suitable solvent. It is obtained by reacting 2.3-buta/diol or its monoester (2) at room temperature in the presence of 2.3-buta/diol or its monoester (2), and then treating this in a conventional manner. Solvents used in the above reaction include ether, tetrahydrofuran, chloroform, benzene, etc., and deoxidizing agents include organic bases such as pyricine, triethylamine, diethylamine, sodium hydrogen carbonate, sodium carbonate, etc.
Examples include alkali metal carbonates such as potassium carbonate.

H30 11 H-c-0-0" - (1) RCOL Z') 1 (2) (In the formula, R represents R1 or R2, and R' represents R2 when R is R1, and R2 when R is R2. (indicates R1) Representative examples of butanediol diesters that can be incorporated into the anti-inflammatory and analgesic agent of the present invention include those listed in the first column.

Next, we present the results of a test on the anti-inflammatory and analgesic effects and reduction of side effects of the anti-inflammatory and analgesic agent of the present invention in comparison with the case of administering a non-steroidal anti-inflammatory analgesic substance alone.

Conditional effects: (1) A group of 5 male Wistar rats with a body size of N160-170f were fasted for 20 hours.

The drugs listed in Table 2 were orally administered. For administration, the nonsteroidal anti-inflammatory analgesic substance was suspended in a 1% sodium carboxymethyl cellulose aqueous solution, and the butanediol diester was emulsified in physiological saline to which 1 to 2'm of polysorbate 80 had been added. 60 minutes after drug administration, the rat's paw volume was measured using a volumetric device, and then 0.1 g of 1% caladenin saline solution was added. was injected subcutaneously into the right hind paw, and the edema intensity 3 hours later was compared with a control group administered with an aqueous solution of monocarpoxymethylcellulose sodium to determine the edema suppression rate.

After 6 hours, the rats were sacrificed, the whole stomach was removed (1'L), and the gastric disorder was determined as the ulcer index (-) according to the method of Sperm et al. The ulcer suppression rate was calculated based on the difference between the diol diester combination group and the diol diester combination group. The results are shown in Table 2.

As shown in Table 2 shown in Table 2 No. 011F, compared to the group administered with a non-steroidal anti-inflammatory analgesic substance alone, the group administered with butanediol diester had no effect on the suppression rate of caladenine floaters. In all cases, a high suppression rate was observed only against the occurrence of ulcers, which is a side effect of non-steroidal anti-inflammatory and analgesic substances, so the combination effect was clearly recognized.

(2) Experiments were conducted using a group of five dY mice weighing 22-261 kg. Butanediol diester and indomethacin were orally administered to mice fasted for 16 hours.
After 0 minutes, a 0.6 thiacetic acid solution was administered to 0.1 q/10 yM cavity circle, and stretching was observed and counted for 15 minutes from 5 minutes later. Note that butanediol diester was emulsified in physiological saline to which 1 to 2 drops of polysorbate 80 was added, and indomethacin was suspended in a 1% sodium carboxymethyl cellulose aqueous solution. This result is the third
Shown in the table.

Table 3 (In the following, compound numbers and dosages are the same as Table 2.) As shown in Table 3, there is a difference in the Taioke effect between the indomethacin base 8 administration group and the butanediol diester' 9F administration group. was not observed, and Oi and @ of the effects of combined use were not enhanced.

The Y self-loss IiK tub agent of the present invention is suitable for the first purchase of a bowl steroid injection and a butanediol diester meeting.
The above may be particularly determined by blending and dosage in a ratio of 1:1 to 1:20.

The anti-inflammatory agent of the present invention can be administered either by mouth or by mouth, and can be administered in various dosage forms, such as powders, tablets, capsules, granules, and liquids. Administration: Can be administered parenterally such as suppositories.

The above-mentioned formulation can be performed by a method known per se. That is, butanediol diester and a nonsteroidal anti-inflammatory analgesic substance are blended, and further excipients such as starch, lactose, and mannitol; binders such as sodium carboxymethyl cellulose and hydroxyzorobil cellulose;
Disintegrants such as crystalline cellulose and calcium carboxymethylcellulose; lubricants such as talc and magnesium stearate; fluidity improvers such as light anhydrous silicic acid, etc. can be appropriately combined to formulate powders, tablets, capsules, or granules. can be manufactured.

Liquid preparations can be made by dissolving butanediol diester and nonsteroidal anti-inflammatory analgesic substances in olive oil, peanut oil, etc., or by adding the compound to water using a nonionic surfactant such as Tween 20 or polysorbate 80. It can be dissolved or suspended in physiological saline or the like to form an aqueous solution. Furthermore, suppositories can be produced by dispersing the dispersion in a commonly used base such as cacao butter, synthetic oil, etc. in a conventional manner and then solidifying it.

The dosage of the anti-inflammatory and analgesic agent of the present invention thus obtained varies depending on the degree of the patient's suffering, but is usually the usual dose of the non-steroidal anti-inflammatory and analgesic substance, i.e., 50 to 75 caps/min for indomethacin. Nikkei Ro administration or 25-100
'lF/time, 1 to 4.5 for suppositories and aspirin
For phenylbutacin, it is preferable to use the same amount as 100 to 400 da/day, and it is preferable to administer this once a day or in several divided doses.

The thus obtained anti-inflammatory and analgesic agent of the present invention is an extremely useful anti-inflammatory agent because it significantly suppresses side effects such as ulcers that occur in the gastrointestinal tract without weakening the main action of the non-steroidal anti-inflammatory and analgesic substance that is the medicinal ingredient. It is a painkiller.

Next, the present invention will be explained with reference to Examples.

Example 1 (tablet) One tablet having the following composition was manufactured according to a conventional method.

Butanediol diester 100”
F (Compound No. 1 in Table 1) Phenylcytacin ioo da light silicic anhydride 100
q crystalline cellulose 6o
qHydroxynorobil cellulose 1o
Takarpoxymethylcellulose calcium 24
1v talc
4Mg total amount 400
Compounding Example 2 (Granules) Granules having the following composition were produced according to a conventional method.

Butanediol diester (compound number 26 in Table 1)
200'Iq/aspirin
200 #Light silicic anhydride
200 q man knit
1200 ■ Starch
180 Cape Zendo
2000 g II Example 3 (Suppository) According to a conventional method, the following composition was melted, stirred, and then molded and solidified to produce one suppository.

Butanediol diester 250W
g (Compound No. 31 in Table 1) Indomethacin 2511F
All children 1,400 capes or more Sand person Nisnis Pharmaceutical Co., Ltd. agent Masu Burishi shoulder negative 3 Shin patent attorney frI3 No Toshio patent attorney Ko Feng Nobuo

Claims (1)

[Claims] 1. A nonsteroidal Tn inflammation analgesic substance and the following formula (■). H3 1i3 [In the formula, R1 and R2 are the same or different and alkyl R
3 represents a hydrogen atom, an alkyl group or a cyano group; 4 represents a phenyl group or a phenyl group substituted with - or two or more groups of a halogen atom, an alkyl group, an alkoxy group or an acyloxy group]; An anti-inflammatory and analgesic agent containing the following 2,3-detanediol diester ws conductor. 2. Non-steroidal anti-inflammatory analgesic substances include indomethacin, aspirin, phenyldetazone, oxyphendetazone, ketophenylbutadine, mefenam #, flufenamic acid, dichloro-7enac sodium, nazoloxene, ibufenac, ibuzolofen, clo7-ezone The anti-inflammatory analgesic agent according to claim 1, which is selected from the group consisting of , ketozolofen.