JPH0665069A - Smooth muscle contraction suppressing agent - Google Patents

Abstract

PURPOSE:To obtain a smooth muscle contraction suppressing agent having high activity by using 4-ethylguaiacol as an active component. CONSTITUTION:The objective suppressing agent is a tablet, injection, etc., containing 4-ethylguaiacol of formula in an amount of 1-500mg/day/kg (preferably 2-25mg/day/kg) for adult for oral or intrarectal administration or 0.2-300mg/ day/kg (preferably 0.5-5mg/day/kg) for adult for parenteral administration such as injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a smooth muscle contraction inhibitor, and more particularly to a smooth muscle contraction inhibitor containing 4-ethylguaiacol as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Phloroglucinol has been known as a compound having a smooth muscle contraction-suppressing action or an antispasmodic action (Merck Index, 11th Edition, 1163).
page). However, its activity is not always sufficient.

[0003]

DISCLOSURE OF THE INVENTION The present invention is to provide a smooth muscle contraction inhibitor having high activity.

[0004]

In view of the above problems in the prior art, the present inventor searched various phenol compounds such as phloroglucinol-related compounds, particularly polyphenols and substituted phenols, and found that Among the compounds, it was found that especially 4-ethylguaiacol has extremely excellent smooth muscle contraction inhibitory activity. The present invention has been completed based on this finding.

That is, the present invention provides a smooth muscle contraction inhibitor containing 4-ethylguaiacol as an active ingredient.

4-Ethylguaiacol, which is the active ingredient of the present invention, is also known as 2-methoxy-4-ethylphenol and is a known compound represented by Chemical formula 1.

[0007]

[Chemical 1]

4-Ethylguaiacol can be easily produced according to a known method and is already on the market.

In the present invention, the above 4-ethylguaiacol is used in the form of a general pharmaceutical preparation. The preparation is prepared according to a conventional method using a commonly used pharmaceutically acceptable excipient or diluent. The formulation of the present invention can be made into various forms depending on the therapeutic purpose, and as typical examples thereof, suitable for oral administration of tablets, pills, powders, capsules, granules, liquid preparations for internal use and the like. Examples include dosage forms, dosage forms suitable for intravascular administration such as injections, intramuscular administration, subcutaneous or intradermal administration, and dosage forms suitable for rectal administration such as suppositories.

In preparing tablets, granules and powders, conventionally known carriers can be widely used. Examples include excipients such as lactose, sucrose, glucose, starch and crystalline cellulose.
For example, binders such as hydroxypropyl cellulose, methyl cellulose, gelatin, tragacanth, gum arabic, sodium alginate, etc., disintegrating agents such as starch, carboxymethyl cellulose, calcium carbonate, etc., lubricants such as magnesium stearate, talc, stearic acid, etc. Can be used.

If necessary, the tablets may be coated with an ordinary coating, for example, sugar-coated tablets, film-coated tablets, and may be bilayer tablets or multilayer tablets.
Granules and powders can also be coated normally.

For the preparation in the form of pills, various carriers conventionally known in this field can be used, and examples thereof include excipients such as licorice powder, glucose and flour, such as glycerin, water and syrup. Binders such as gum arabic, tragacanth and gelatin, and disintegrating agents such as medicinal yeast, arrowroot and laminaria powder are used.

For the preparation in the form of capsules, various carriers conventionally known in this field, for example, excipients such as lactose, olive oil and soybean oil are used.

The liquid preparation for internal use is an aqueous or oily suspension, solution,
Syrup or other forms may be used. For such liquid preparations, commonly used additives such as suspending agents such as sorbit syrup, methyl cellulose, gelatin, carboxymethyl cellulose, emulsifying agents such as lecithin and gum arabic can be used.

When prepared in the form of injectables, the compositions may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, suspending, stabilizing and dispersing agents. Such a formulation may be included.

For the preparation in the form of suppositories, conventionally known carriers can be widely used. For example, bases such as cacao butter, glycerogelatin, macrogol and the like can be used. For suppositories, an emulsifying agent and a suspending agent can be used if necessary. Further, a coloring agent, a flavoring agent and the like can be added to the preparation of the present invention, if necessary.

The amount of 4-ethylguaiacol contained in the preparation of the present invention is not particularly limited and may be appropriately selected, but is generally about 0.2 to 60% of the total weight of the preparation.

The dose of the pharmaceutical preparation of the present invention is appropriately selected according to the sex, age, body weight, degree of symptoms, etc. of the patient. Generally, in the case of oral administration and rectal administration, it is effective for adults. 4-ethyl guaiacol as a component is about 1 to 500 mg, preferably about 2 to 100 mg, and more preferably 2 to 25 mg per 1 kg of body weight per day.
It should be about.

When parenterally administered as an injection, 4-ethylguaiacol, which is an active ingredient for an adult, is generally about 0.2 to 300 mg, preferably about 0.2 to 50 mg per 1 kg of body weight per day. More preferably, it may be about 0.5 to 5 mg. The formulation of the present invention may be administered in 2 to 4 divided doses per day.

[0020]

INDUSTRIAL APPLICABILITY The preparation of the present invention has various smooth muscles such as intestinal tract, bile duct, ureter, stomach, uterus, blood vessel, etc., based on the excellent inhibitory effect on smooth muscle contraction of 4-ethylguaiacol as an active ingredient. Suppress the contraction of.

As a result, in humans and animals, various conditions requiring inhibition of smooth muscle contraction, such as gastric antrum and intestinal spasm, tonic dyskinesia of the biliary tract, bile duct stones, gallbladder stones, urinary stones, menstruation. It is effective in alleviating pain caused by pain, and is also effective in treating diarrhea, abdominal pain, etc. due to intestinal motility because it suppresses the movement of the intestinal tract, which is a smooth muscle.

[0022]

[Examples] Formulation examples and the results of pharmacological tests are shown below.

The kneaded each component of Formulation Example 1 pill Ingredients Amount (mg) 4-ethyl guaiacol 50 Licorice 25 Glycerin 10 Tsunemizu 50 prescriptions, splits the pill mass in Setsumaru machine, Narumaru machine Narumaru with 1 round 4-ethyl guaiacol 5
Pills containing 0 mg were prepared.

[0024] Formulation Example 2 Capsules Ingredient Quantity (mg) 4-ethyl guaiacol 100 Starch 250 4-ethyl guaiacol and the starch were mixed, a mixed powder, and filled into hard capsules, in one capsule 4- A hard capsule containing 100 mg of ethyl guaiacol was prepared.

The dissolved Formulation Example 3 Capsules Ingredient amount (mg) 4-ethyl guaiacol 100 olive 200 4-ethyl guaiacol in olive oil to give a solution and filled in soft capsules, in one capsule 4-ethyl guaiacol 100mg A soft capsule containing was prepared.

[0026] Formulation Example 4 Tablets Ingredient Quantity (mg) 4-ethyl guaiacol 150 the components other than magnesium stearate such that the lactose 250 cellulose 3 Magnesium stearate 2 months Robo carboxymethyl cellulose 10 above formulation were mixed, and this Knead with water to give granules, which are dried and then mixed with magnesium stearate and compression-molded, or the components of the above formulation are mixed and directly compression-molded to give tablets of 415 mg each. Was prepared.

[0027] After dissolving Formulation Example 5 Injection Ingredient amount (mg) 4-ethyl guaiacol 50 distilled water for injection 2 ml 4-ethyl guaiacol 50mg in distilled water for injection, an injection with a sealing and sterilizing the preparation did.

Pharmacological test 1 24 Wistar female rats weighing 150 to 200 g
Fasted for an hour, pentobarbital sodium (body weight 1
Anesthesia was performed by intramuscular injection (30 mg / kg). A midline incision was made in the abdomen, the small intestine was removed, 15 cm was removed from the ileocecal region, and the ileum was excised as a piece of about 4 cm. The piece of ileum was washed with Tyrode's solution, and then suspended in a Magnus chamber (KN-207, manufactured by Natsume, Tokyo) filled with 50 ml of Tyrode's solution saturated with air overnight.
At this time, the Tyrode's solution was maintained at 37 ° C., and air was flown at a rate of 0.2 ml per second. Spontaneous contraction of the ileum piece was measured using a isotonic Hebel
KN-215, manufactured by Natsume).

The phenol compounds shown in Table 1 were cumulatively administered to the above-mentioned Magnus chamber every 3 minutes, and the contraction of the intestinal tract was measured each time. The degree of contraction of the intestinal tract was measured as the average height of the main peak at each dose, and the contraction of each dose as a percentage of the average peak height (100%) when the dose of each phenolic compound was 0 g / ml. The ratio was calculated and the concentration of each phenolic compound at which the contraction was suppressed by 50%, that is, IC ₅₀ was determined. The results are shown in Table 1.

[0030]

[Table 1]

The IC _{50 for} most phenolic compounds is
While it is on the order of 10 ^-5 to 10 ^-4 g / ml, 4
Only the IC _{50 of} ethyl guaiacol is of the order of 10 ⁻⁶ g / ml.

Therefore, it is understood that 4-ethylguaiacol is an excellent smooth muscle contraction inhibitor because it has a particularly high intestinal tract contraction inhibitory action.

Pharmacological test 2 Acetylcholine, serotonin, prostaglandin E ₁ , E ₂ , F1α, F acting as agonists (agonists)
The inhibitory effect of 4-ethylguaiacol on the intestinal contraction induced by 2α, bradykinin or histamine,
The measurement was performed using the same device as in the above pharmacological test 1. However, instead of air, a mixed gas of 95% oxygen and 5% carbon dioxide was passed.

After ileal pieces of Wistar rats obtained in the same manner as in the above-mentioned Pharmacological Test 1 were suspended in a Magnus chamber, and the neurotransmission inhibitor tetrodotoxin was added to Tyrode's solution to a final concentration of 0.5 μM. Equilibrate for 30 minutes. Acetylcholine is added to the Magnus chamber to a final concentration of 0.7 μM, and the peak height of intestinal contraction is measured (control).

Then, after washing the ileum pieces, 4-ethylguaiacol was added to Tyrode's solution to a final concentration of 33 μM, and the peak height of contraction at this time was measured.

Thereafter, after washing the ileum pieces in the same manner, the final concentrations of 4-ethylguaiacol were 66 μM, 165 μM,
The peak height of each contraction induced by 0.7 μM of acetylcholine when measured at 330 μM and 660 μM respectively was measured. Control peak height (1
The percentage of the peak height at each 4-ethylguaiacol concentration relative to (00%) was calculated, and from the thus obtained 4-ethylguaiacol concentration-contraction curve, the 4-ethylguaiacol concentration IC required to suppress the contraction by acetylcholine by 50% was calculated. I asked ₅₀ .

Hereinafter, serotonin, prostaglandins E ₁ , E ₂ , F1α, F2α, bradykinin, and histamine are also final concentrations of serotonin 10 μM, prostaglandins 1 μM, bradykinin 0.1 μM, and histamine 100 μM. IC ₅₀ was measured by the same method as for acetylcholine.

The results are shown in Table 2 below.

[0039]

[Table 2]

As is clear from Table 2, 4-ethylguaiacol has an inhibitory effect on intestinal contraction caused by each agonist.

Pharmacological Test 3 (a) Wistar rat ileal pieces obtained in the same manner as in Pharmacological Test 1 were washed with a calcium-free solution (Tyrode's solution prepared without calcium chloride) and immersed for 1 hour. The piece of ileum was suspended in a device similar to the above-mentioned Pharmacological Test 2 (however, the Magnus chamber was filled with 50 ml of a calcium-free liquid), and ethylene glycol bis (β-aminoethyl ether) -N, N, N was suspended. ′, N′−
Tetraacetic acid (EGTA) was added to a final concentration of 0.1 mM, and tetrodotoxin was added to a final concentration of 0.5 μM. After equilibrating for 30 minutes, potassium chloride was added to a final concentration of 22.7 mM, and after confirming that intestinal contraction did not occur, calcium chloride was cumulatively administered. The degree of intestinal contraction that occurred after each administration was measured on a chemography. The results are shown in Fig. 1.

From FIG. 1, it was confirmed that intestinal contraction increases with an increase in calcium. The fact that intestinal contraction depends on calcium concentration indicates that the intestinal contraction is due to smooth muscle.

(B) In the same manner as in the above pharmacological test 2,
Final concentration of potassium chloride 2 instead of acetylcholine 2
In addition to 2.7 mM, the inhibitory effect of 4-ethylguaiacol on contraction due to potassium depolarization was measured. As in the case of Pharmacological test 1, the contraction rate was the average peak height (100%) when the dose of 4-ethylguaiacol was 0M.
Was obtained as a percentage of. The results are shown in Figure 2.

(C) Next, in the same manner as in (b) above, ionomycin, which is a calcium ionophore, was added in place of potassium chloride so that the final concentration was 1 μM, and suppression of ionomycin-induced contraction by 4-ethylguaiacol was performed. The effect was measured. The contraction rate was obtained as a percentage of the average peak height (100%) when the dose of 4-ethylguaiacol was 0 M, as in Pharmacological Test 1. The results are shown in Fig. 3.

When potassium chloride is added, potassium depolarization is caused to open the calcium channel in the cell membrane of smooth muscle, the intracellular calcium ion concentration is increased, and contraction is induced.

On the other hand, ionomycin acts as a carrier for the inflow of calcium into the cell from the outside of the cell membrane of smooth muscle, increases the intracellular calcium ion concentration, and causes contraction.

As shown in FIGS. 2 and 3, 4-ethylguaiacol inhibits both these different contractions of action. Therefore, it is understood that 4-ethylguaiacol has an antispasmodic effect that suppresses smooth muscle movement.

[Brief description of drawings]

FIG. 1 is a kimograph showing the results of pharmacological test 3 (a).

FIG. 2 is a graph showing the results of pharmacological test 3 (b).

FIG. 3 is a graph showing the results of pharmacological test 3 (c).

Claims (1)

[Claims] 1. A smooth muscle contraction inhibitor containing 4-ethylguaiacol as an active ingredient.