JPH05952A - Pharmaceutical composition containing torasemide - Google Patents

Abstract

PURPOSE: To obtain the subject composition useful for a preparation for oral administration, excellent in characteristics, by formulating torasemide or its salt as a main agent with hydroxypropyl cellulose and croscarmellose sodium. CONSTITUTION: This medicine composition for oral administration is obtained by formulating (A) 0.1-20 pts.wt., especially 1-10 pts.wt. of torasemide or its salt useful for preventive and therapeutic agent for hypertension and edema, diuretic, etc., with (B) 1-10 pts.wt., especially 2-5 pts.wt. of hydroxypropyl cellulose and (C) especially 1-20 pts.wt., especially 5-10 pts.wt. of croscarmellose sodium. The composition is capable of improving storage stability of torasemide of its own, change in appearance of preparation by moisture absorption, absorption of torasemide and in its turn, bioavailability.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to prevention of hypertension and edema.
The present invention relates to a pharmaceutical composition containing torasemide which is useful as a therapeutic agent, a diuretic agent and the like.

[0002]

BACKGROUND OF THE INVENTION Torasemide [chemical name, 1-isopropyl-3- (4-m-toluidino-3-pyridyl) sulfonyl] urea] is useful as a diuretic for treating hypertension. Is. As the oral administration preparation containing torasemide, the main drug is, for example, sugar, starch, starch derivative, cellulose, cellulose derivative,
It is known that a conventional auxiliary agent such as a release agent or an anti-adhesive agent is added to formulate in a conventional manner. For example, it is administered as a tablet containing lactose, corn starch, silicon dioxide and magnesium stearate. (JP-A-62-455
No. 76 published patent).

On the other hand, especially when stored for a long period of time, the storage stability of torasemide itself is improved, the change in the appearance of the preparation due to moisture absorption is improved, and the absorbability of torasemide from the digestive tract is further improved, resulting in excellent bioavailability. The advent of pharmaceutical formulations is desired. Therefore, it is an object of the present invention to solve such problems of the prior art and to provide an oral preparation containing an excellent torasemide.

[0004]

[Means for Solving the Problems] In order to solve the above problems, the present inventors selected a specific component from a large number of components such as general binders, disintegrants, excipients, dispersants, and solubilizers. As a result of wide-ranging investigations on the combination, combination ratio, dissolution rate, disintegration degree, main drug stability, main drug absorbability, etc., a composition containing torasemide, hydroxypropylcellulose and croscarmellose sodium, and further lactose or / and crystals. A composition in which an excipient such as cellulose and a lubricant such as magnesium stearate are selectively combined, and further, a pharmaceutical composition containing these in a fixed ratio all have excellent properties as a preparation for oral administration. Heading out, the present invention has been completed.

That is, the present invention relates to a pharmaceutical composition containing torasemide, hydroxypropyl cellulose and croscarmellose sodium, and particularly preferably 0.1 to 20 parts (hereinafter, parts by weight) of torasemide, a highly substituted hydroxy. The present invention relates to a pharmaceutical composition containing 1 to 10 parts of propylcellulose and 1 to 20 parts of croscarmellose sodium.

In the present invention, as the torusemide, 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, and the like. The salt of toracemide is not particularly limited as long as it is pharmacologically acceptable, and for example, acetic acid, corkic acid, maleic acid, fumaric acid, malic acid, tartaric acid, salts with organic acids such as metasulfonic acid, hydrochloric acid, Illustrative are salts with inorganic acids such as hydrobromic acid, phosphoric acid and sulfuric acid.

In the present invention, hydroxypropyl cellulose is selected as the binder, and it has been found that those having a high degree of substitution are particularly preferable. The degree of substitution of such highly substituted hydroxypropyl cellulose is usually 50 to 80%, preferably 60, as the content (%) of hydroxypropoxyl groups.
~ 70%. Specifically, hydroxypropyl cellulose (Pharmacopoeia product) is used.

The pharmaceutical composition of the present invention further comprises an excipient,
Lubricants and the like may be added, and the excipients include lactose,
Crystalline cellulose or the like is preferably used, and magnesium stearate or the like is preferably used as the lubricant.

The compounding ratio of each component in the pharmaceutical composition of the present invention is usually 0.1 to 20 parts (hereinafter, parts by weight) of toracemide, preferably 0.5 to 15 parts, more preferably 1 part.
-10 parts, hydroxypropyl cellulose 1-10 parts,
Preferably 2-5 parts, croscarmellose sodium 1
-20 parts, preferably 3-15 parts, more preferably 5 parts
-10 copies. The amount of the other components to be added to the pharmaceutical composition of the present invention is 10 to 150 parts by weight of the excipient, preferably 7 parts.
The amount is 0 to 140 parts, more preferably 100 to 130 parts, the lubricant is 0.1 to 5 parts, preferably 0.2 to 2 parts, and more preferably 0.5 to 1.5 parts.

The pharmaceutical composition of the present invention is preferably orally administered as a prophylactic / therapeutic agent for hypertension and edema, a diuretic agent and the like. The pharmaceutical composition of the present invention is prepared by mixing each component by a conventional method,
It is formulated as powder, fine granules, granules and tablets.

The dose of the pharmaceutical composition of the present invention varies depending on the sex, weight, age, symptom, etc. of the patient, but in general, the daily dose for an adult is about 1 to 30 mg as torasemide. It is administered in 1 to several divided doses per day.

[0012]

EXAMPLES Examples and experimental examples will be given below to specifically describe the present invention, but the present invention is not limited thereto.

Example 1 40 g of torasemide, 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 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.

Experimental Example 1 According to Example 1, 6 types of preparations having the compositions shown in Table 1 were prepared. In the table, No. 1 shows an example of the present invention, and No. 2 and later show comparative examples.

[0016]

[Table 1]

Disintegration time and dissolution rate of each composition (30 minutes)
Based on the dissolution test of the 11th revised Japanese Pharmacopoeia
Table 2 shows the results of the examination under the conditions of 500 ° C and ° C.

[0018]

[Table 2]

Tables 3 to 5 show the results of examining the appearance, hardness and weight change of each composition after allowing it to stand for 14 days under the conditions of 40 ° C. and 75% relative humidity.

[0020]

[Table 3]

[0021]

[Table 4]

[0022]

[Table 5]

Table 6 shows the results of examining the content of related substances after each composition was stored at 60 ° C. for one month.

[0024]

[Table 6]

Experimental Example 2 The composition of the present invention (No. 1) was orally administered to dogs (body weight: 8 to 12 kg, number of cases: 6) in an amount of 4 mg as torasemide.
The area under the blood concentration curve of torasemide up to the 4th hour is 4
It was 0.5 ± 7.8 (μg / ml · hr).

[0026]

Industrial Applicability As described above, the torsemide-containing pharmaceutical composition of the present invention comprises torasemide or a salt thereof as a main drug, and by selecting hydroxypropyl cellulose and croscarmellose sodium, the storage stability of torasemide itself, It has the effect of improving the appearance of the preparation due to moisture absorption, improving the absorbability of torasemide, and consequently the bioavailability.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Masahiro Kikuchi             1-1,2-1180 Otani, Hirakata-shi, Osaka Prefecture               Midori Cross Central Research Institute Co., Ltd. (72) Inventor Yuko Zhu             1-1,2-1180 Otani, Hirakata-shi, Osaka Prefecture               Midori Cross Central Research Institute Co., Ltd. (72) Inventor Nobuo Kondo             1-1,2-1180 Otani, Hirakata-shi, Osaka Prefecture               Midori Cross Central Research Institute Co., Ltd. (72) Inventor Koichi Yamauchi             1-1,2-1180 Otani, Hirakata-shi, Osaka Prefecture               Midori Cross Central Research Institute Co., Ltd. (72) Inventor Kazumasa Yokoyama             1-1,2-1180 Otani, Hirakata-shi, Osaka Prefecture               Midori Cross Central Research Institute Co., Ltd.

Claims (2)

[Claims] 1. A pharmaceutical composition containing torasemide or a salt thereof, hydroxypropyl cellulose and croscarmellose sodium. 2. A pharmaceutical composition containing 0.1 to 20 parts (hereinafter, parts by weight) of toracemide, 1 to 10 parts of hydroxypropyl cellulose, and 1 to 20 parts of croscarmellose sodium.