JPH0232016A - Srs-a isolation inhibiting agent - Google Patents

Abstract

PURPOSE:To obtain SRS-A (slow reacting substance of anaphylaxis) isolation inhibiting agent containing synephrine as an active ingredient and useful in remedy for chronic obstructive pulmonary disease. CONSTITUTION:The aimed agent containing synephrine expressed by the formula as an active ingredient. Synephrine can be administered directly or together with a conventional preparation carrier and properly used as an oral agent such as tablet, capsule, granule, subtilized granule or inhalant or parenteral agent such as injection or ointment and the dose is 30-700mg daily.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a drug effective for the treatment of chronic obstructive pulmonary disease.

[Prior Art and Problems] SRS is an important chemical mediator that induces attacks of allergic obstructive respiratory diseases, such as asthma.
-A (slow reacting 5ubstan
ce oranaphylaxis) is known to have pharmacological effects such as strong bronchial spasm effects. Since there is a close relationship between the release of 5R8A and bronchial obstruction during asthma attacks, inhibiting the release of SRS-A may lead to the fundamental treatment of allergic obstructive respiratory diseases. it is conceivable that. Therefore, it has been desired to develop a drug that suppresses the release of 5F (SA).

[Means for Solving the Problems] As a result of searching for a substance that suppresses the release of SRS-A, the present inventors discovered that synephrine has an effect of suppressing the release of 5R5A, and completed the present invention. That is, the present invention is an SRS-A release inhibitor containing synephrine as an active ingredient.

S RS biosynthesized in the arachidonic acid cascade
-The main body of A is leukotriene C4, leukotriene D4
, leukotriene E4, but it was not known at all that synephrine inhibits the release of these chemical mediators.

Synephrine is a compound having the structure shown below, for example, Aldrich (Al
drich) can be used.

[Effects of the Invention] The fact that cosynephrine has an effect of inhibiting 5R5-A release will be explained with reference to experimental examples.

Experimental example ■ Sensitization of guinea pig lungs Hartley (Hartley
) type guinea pigs were hit on the head, the cervical aorta was incised, and the animals were bled to death. Next, the heart-lung specimen was promptly removed (9), and Krebs' solution was injected into the pulmonary artery to wash out the blood, and the lung tissue was cut out, excluding the visible large blood vessels and airways.
Several sections of 00Q were prepared. These tissue sections were
7℃, 95% 0. Passive sensitization was performed by incubating for 3 to 4 hours with anti-ovalbumin serum (produced from Japanese white rabbit, antibody titer: 5000 times) diluted with Krebs' solution under saturated mixed gas of 5% COt and 5% COt.

■Release of S RS-A from sensitized lungs After washing the sensitized lung tissue as described above with Krebs' solution, synephrine was added at varying concentrations for 10 minutes.
The mixture was incubated at 0.degree. C., and then the antigen, ovalbumin 0.5719, was added and further incubated for 10 minutes. In order to stop the reaction, the reaction solution was quickly cooled with water and filtered through a glass filter.
was used for measurement.

■Measurement of S RS-A A 3x8u longitudinal muscle was cut out from the guinea pig ileum in the range of 5 to 1Oα, excluding 5eR from the ileocecal region, and 95% 0. The specimen was suspended in Krebs liquid at 37°C under a mixed gas saturation of 5% CO1, connected to a transducer, and subjected to a load of 50019.The Krebs liquid was exchanged several times until spontaneous movement disappeared, and the specimen was left for a while. . Thereafter, the reaction solution obtained in step (3) was applied, and the tension of the contraction reaction was recorded with a recorder. S
Calculate the inhibition rate of RS-A release. As a result, 2 x 10-
When 5M was added, SRSAall was suppressed by 54.9%.

Next, an acute toxicity test of synephrine was conducted using ddY mice, and no deaths occurred even after 9 doses of 500119/.

The above results confirmed the usefulness of synephrine as a 5Rs-Aal inhibitor.

Next, the dosage and formulation of synephrine will be explained.

Synephrine can be administered to animals and humans either neat or with conventional pharmaceutical carriers.

The dosage form is not particularly limited and may be selected and used as required, including tablets, capsules, granules, fine granules,
Examples include oral preparations such as powders, parenteral preparations such as injections, and suppositories.

In order for an oral drug to have the desired effect, an adult dose of synephrine is usually 30 to 700 q, depending on the age, weight, and severity of the disease. It seems appropriate to take the drug in divided doses several times a day.

Oral agents include, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant co-starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, individually substituted hydroxypropyl starch.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sugar fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoters: light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

Synephrine can also be administered as a suspension, emulsion, tablet, or elixir, and these various forms may contain flavorings and coloring agents.

In order to achieve the desired effect as a parenteral agent, it is usually necessary for adults to administer up to 5 to 45 mg of synephrine per day by intravenous injection or intravenous drip, although this will vary depending on the patient's age, weight, and degree of disease. , subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include external solutions, ointments such as ointments, omentum for intrarectal administration, etc., and are manufactured according to conventional methods.

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited in any way by this.

Example 1 ■Corn starch 24.99 ■Crystalline cellulose 15.09 ■Carboxymethylcellulose calcium 2.09 ■Light silicic anhydride 0.2g■Magnesium stearate 0.49■Synephrine
7.5 g total 50.09 According to the above recipe, ① to ② were mixed uniformly and compressed using a tablet machine to obtain some 200 xti tablets.

These tablets contain synephrine 30+yy, and adults should take 1 to 23 tablets a day in several doses.

Example 2 ■ Crystalline cellulose 40.259 ■ Magnesium stearate 0.259 ■ Calcium carboxymethyl cellulose 2. OOg ■ Synephrine 7.50y total 50
．． 009 According to the above recipe, mix ■, ■, and part of ■ uniformly, compression mold it, crush it, add the remaining amount of ■ and ■, mix it, and compression mold it with a key press to make a part of 2001+9. tablets were obtained.

These tablets contain synephrine 30XIF, and adults should take 1 to 23 tablets a day in several doses.

Example 3 ■ Crystalline cellulose 15.259 ■ 10% hydroxypropyl cellulose ethanol solution 25.009 ■ Carboxymethyl cellulose calcium 2.00 g ■ Magnesium stearate 0.25 g ■ Synephrine
7. fI total: 50.009 According to the above recipe, ■, ■, and ■ are mixed uniformly, and they are netted by a conventional method, granulated using an extrusion granulator, dried and crushed, and then ■ and ■ are mixed. A portion of the mixture was compressed and molded using a tablet machine to obtain 200 R9 tablets.

This tablet contains Cinemarin 30 Shoulder 9, and adults should take 1 to 23 tablets a day in several doses.

Example 4 ■Corn starch 39.99■Magnesium stearate 0.49■Carboxymethyl cellulose calcium 2.09 ■Light silicic anhydride 0.29■Synephrine
7.5 g total 50.09 According to the above recipe, ① to ② were mixed uniformly, compression molded using a compression molding machine, crushed using a crusher, and sieved to obtain granules.

This granule Iso contains Cinemarin 150 Shoulder 9, and is taken by adults at 0.2 to 4.6 g per day in several doses.

Example 5 ■ Crystalline cellulose 17 g ■ 10% hydroxypropyl cellulose ethanol solution 259 ■ Synephrine 8 g Total 50 g According to the above recipe, ■ to ■ were mixed uniformly and made into a paste. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

This granule 19 contains synephrine 160 R9, and is taken by adults in 0.2 to 4.39 doses per day in several doses.

Example 6 ■Corn starch 41.51F■Light silicic acid anhydride 0.29■Synephrine
8.3 Li meter so, og Mix ■～■ uniformly according to the above recipe, 20019
was filled into a No. 2 capsule.

This capsule contains synephrine 33.2N.
It contains 1 to 21 capsules per day for adults, divided into several doses.

Example 7 ■ Distilled water for injections ■ Glucose 20011? ■Synephrine 20119 total amount
5d After dissolving ■ and ■ in distilled water for injection, they were injected into the ampoule of 5- and autoclaved at 121° C. for 15 minutes to obtain an injection.

Claims (1)

[Claims] An SRS-A release inhibitor containing synephrine as an active ingredient.