JPH05170741A - Thromboxane a2 antagonist - Google Patents

Abstract

PURPOSE:To provide a thromboxane A2 antagonist containing torasemide as an active ingredient and useful for preventing or treating thrombosis, stenocardia, bronchial asthma, etc. CONSTITUTION:The antagonist contains torasemide: 1-isopropyl-3-[4-m- toluidino-3-pyridyl) sulfonyl] urea or its salt as an active ingredient. A medicinal composition containing 0.1-20 pts.wt. of the tracemide, 1-10 pts.wt. of highly substituted hydroxypropyl cellulose and 1-20 pts.wt. of crosscarmelose sodium salt is preferable.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel use of torasemide or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Torasemide [chemical name: 1-isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea] is Na ⁺ or Cl in renal tubule of kidney. ^It suppresses reabsorption of-, resulting in a stronger diuretic effect than other diuretics, such as furosemide. Further, toracemide has the advantage that it does not disturb the electrolyte balance in the body and excretes K ⁺ very little. Therefore, torasemide is applied as a diuretic for cardiac / renal edema, pulmonary edema, premenstrual tension, and as a hypotensive agent for the prevention / treatment of various hypertension. The object of the present invention is to provide new uses for this torasemide.

[0003]

[Means for Solving the Problems] In order to solve the above problems, the present inventors have conducted extensive studies on the mechanism of action of torasemide, and found that they newly have a thromboxane A ₂ antagonistic action, As a result of further earnest research, the present invention has been completed. That is, the present invention is a thromboxane A ₂ antagonist containing torasemide or a salt thereof as an active ingredient.

In the present invention, as the toracemide, for example, white crystals having a melting point of 163 to 164 ° C., and a melting point of 1 are preferable.
Columnar crystals having a melting point of 162 ° C. and columnar crystals of 69 ° C. are used. A method for producing torasemide is disclosed in JP-A-50-1425.
No. 71, JP-A No. 62-45576, etc. are exemplified. The salt of toracemide is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include salts with organic acids such as acetic acid, corkic acid, maleic acid, fumaric acid, malic acid, tartaric acid and methanesulfonic acid, and hydrochloric acid. Examples thereof include salts with inorganic acids such as hydrobromic acid, phosphoric acid and sulfuric acid.

[0005] Examples of the preparation containing the torasemide of the present invention or a salt thereof include oral preparations, injection preparations and suppositories. For example, an orally-administered preparation containing torasemide or a salt thereof contains a main drug, torasemide, such as sugar, starch, starch derivative, cellulose, cellulose derivative,
It is manufactured by adding a general auxiliary agent or additive such as a release agent or an anti-adhesive agent and formulating it by a conventional method. In particular, it is preferably administered as a tablet containing lactose, corn starch, silicon dioxide and magnesium stearate (see JP-A-62-45576).

Further, as a preferred example of the present invention, a pharmaceutical composition containing torasemide, hydroxypropylcellulose and croscarmellose sodium, particularly preferably 0.1 to 20 parts of torasemide (hereinafter referred to as “part by weight”), highly substituted A pharmaceutical composition containing 1 to 10 parts of hydroxypropyl cellulose and 1 to 20 parts of croscarmellose sodium is exemplified. The degree of substitution of the highly substituted hydroxypropyl cellulose is typically 50 to 80%, preferably 60 to 70%, as the content (%) of hydroxypropoxyl groups, and specifically, hydroxypropyl cellulose (Pharmacopoeia product). Is exemplified.

The formulation of the present invention may further contain an excipient, a lubricant and the like. As the excipient, lactose, crystalline cellulose and the like are preferably used, and as the lubricant, stearin is used. Magnesium acid or the like is preferably used.

The blending ratio of each component of the preferred preparation in the present invention is usually 0.1 to 20 parts (hereinafter, weight part) of torasemide or a salt thereof, preferably 0.5 to 15 parts, more preferably 1 to 10 parts, Hydroxypropyl cellulose 1
-10 parts, preferably 2-5 parts, croscarmellose sodium 1-20 parts, preferably 3-15 parts, and more preferably 5-10 parts. The amount of the other components to be blended is 10 to 150 parts, preferably 70 to 140 parts, more preferably 100 to 130 parts, 0.1 to 5 parts, preferably 0.2 to 2 parts of a lubricant. More preferably 0.5 to 1.5
It is a department. Mixing each of these components by the usual method,
It is formulated as fine granules, granules, and tablets.

Other injections and suppositories containing torasemide or a salt thereof are also prepared by a conventional method, for example, an alkaline buffer and an organic solvent (polyethylene glycol,
Glycerin, alcohol, etc.) may be added to give an injection (see JP-A-63-23818).

The dose of torasemide or a salt thereof varies depending on the sex, weight, age, symptom and the like of the patient, but in general, the daily dose for an adult is about 1 to 30 mg. Administer in several divided doses.

[0011]

INDUSTRIAL APPLICABILITY Toracemide and its salts have a strong thromboxane A ₂ antagonistic action, and are useful for the prevention or treatment of thrombosis, angina, bronchial asthma and the like. Examples and test examples will be given below to specifically describe the present invention.

[0012]

【Example】

Example 1 40 g of toracemide, 1064 g of lactose, and hydroxypropyl cellulose (hydroxypropoxyl group content 62%)
32 g and croscarmellose sodium 24 g were mixed, granulated with water, dried and sieved. This one 466g
Croscarmellose sodium (12.9 g) and magnesium stearate (3.2 g) were mixed with each other and tableted by a conventional method. By this operation, about 2300 tablets each containing 4 mg of torasemide were prepared.

Example 2 Tablets were prepared according to Example 1 using crystalline cellulose instead of lactose.

[0014]

[Test example]

Test Example 1 1) Test method Wistar normotensive rats (NTR, male, body weight about 3)
Immediately after slaughtering 50 g), the thoracic aorta was removed, and a spiral specimen (width: about 3 mm) was used for Krebs-Henseleit solution (Kreb).
Isometric tension was measured by suspending in a 20 ml Magnus tank filled with s-Henseleit under aeration of 95% O ₂ + 5% CO ₂ . The static tension was 1.0 g. Vasoconstrictor [Carbocyclic thromboxane A ₂ (CT
A ₂ )] was added to the Magnus tank, and after the specimen contracted and became stable, torasemide was accumulated (10 ⁻⁷ to 10 ⁻⁴ M) cumulatively.
Was administered to The control drug is indapamide (10 ^-7 to 10 ^-4
M) was used. The tension obtained by subtracting the tension due to complete relaxation by ^10-4 M of papaverine from the tension generated by the vasoconstrictor was taken as 100%, and the relaxation rate at each concentration of toracemide and indapamide was relatively expressed.

2) Results Torasemide dose-dependently relaxed contraction by vasoconstrictor (Table 1). Especially, at 3 × 10 ⁻⁵ M to 10 ⁻⁴ M, the contraction of the vasoconstrictor was significantly relaxed. Also,
The relaxing effect of toracemide on the vasoconstrictor was significantly stronger at 3 × 10 ⁻⁵ M to 10 ⁻⁴ M than that of indapamide.

[0016]

[Table 1]

Test Example 2 1) Test Method Immediately after slaughtering a dog (body weight: 10 to 11 kg), coronary arteries, renal arteries and common iliac arteries were excised, and a spiral specimen (width: about 3 mm)
Was suspended under aeration of 95% O ₂ + 5% CO _{2 in} a 20 ml Magnus tank filled with Krebs-Hensleit solution, and the isometric tension was measured. The static tension was 1.0 g. After stabilizing,
Washing was performed when KCl (30 mM) was administered and maximum contraction was obtained. After repeating this operation at least once, a derivative of TXA ₂ (CTA ₂ : 2 × 10 ^-8 M) was administered. After the maximum contraction was obtained, torasemide, furosemide and indapamide were cumulatively added, and how the isometric tension was changed was measured. The results are shown in Table 2.

[0018]

[Table 2]

2) Results The reactivities of the following four types of canine arteries with trasemide to CTA ₂ were in the order of renal artery> external iliac artery> mesenteric artery> coronary artery. For KCl, the order was renal artery> external iliac artery> mesenteric artery> carotid artery> coronary artery. Only the carotid artery did not respond to CTA ₂ . Torasemide concentration-dependently relaxed CTA ₂ contraction in all four types of canine arteries used this time. Also, Torasemide is 3 ×
At 10 ⁻⁵ M to 10 ⁻⁴ M, it was significantly relaxed to furosemide and indapamide. This relaxation response was strong in the renal and mesenteric arteries, but weak in the coronary arteries.

Front page continuation (72) Inventor Minori Okita 2-25-1 Otani Otani, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd. (72) Masahiro Watanabe 2-25-1 Otani, Hirakata City, Osaka Prefecture No. Ltd. Midori Cross Central Research Institute

Claims (1)

[Claims] 1. A thromboxane A ₂ antagonist comprising torasemide or a salt thereof as an active ingredient.