JPS63183533A - Oral cephalosporin composition - Google Patents

Abstract

PURPOSE:To obtain an oral cephalosporin composition having excellent antibacterial action on both Gram-positive bacteria and Gram-negative bacteria, showing improved absorption in fasting and after meal, containing cephalosporin or an acid addition salt thereof and an organic acid as active ingredients. CONSTITUTION:Pivaloyloxymethyl 7beta-[2-(2-aminothiazol-4-yl)-2-methoxy- iminoacetamido]-3-[(-5-methyl-2H-tetrazol-2-yl) methyl]-3-cephem-4-carboxylate or an acid addition salt thereof and >= twice, preferably 2-3 times as much 2-6C organic acid (e.g. ascorbic acid) as the carboxylate or the salt are blended with additives and pharmaceutically manufactured by a conventional procedure to give the aimed substance. The substance is made into a dosage form such as tablet, capsule agent, granule, pill, fine granule, powder, syrup, etc. A dose is 10-800mg/day calculated as T-2525 for adult and administered dividedly once - several times.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to oral cephalosporin compositions.

In more detail, pivaloyloxymethyl 7β-[2-
(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[(5-methyl-2H-tetrazol-2-yl)methyl]-3-cephem-4-
Carboxylate (hereinafter referred to as T-2588) or an acid addition salt thereof and a compound having 2 to 2 carbon atoms or more than twice the weight of the carboxylate (hereinafter referred to as T-2588)
The present invention relates to an oral cephalosporin composition containing 6 organic acids.

[Prior Art] T-2588 or its acid addition salt is rapidly absorbed from the gastrointestinal tract, and immediately after absorption, the ester of the carboxyl group at the 4-position is hydrolyzed by enzymes in the body, resulting in the corresponding free carboxylic acid compound, i.e., 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamidoco-3-[(5-methyl-2d-tetrazol-2-yl)methyl]-3-cephem-4-carvone Acid (hereinafter referred to as
It is called T-2525. ) is generated. This T-252
5 is an extremely excellent compound with a wide antibacterial spectrum against Durham-positive and Durham-negative bacteria (Japanese Patent Publication No. 60-52755); No oral cephalosporin composition containing an organic acid having 2 to 6 carbon atoms is known.

[Problems to be Solved by the Invention] Subsequent research revealed that the oral absorption of T-2588 or its acid addition salts is affected by meals, and in particular, the absorption rate is lower when fasting than after meals. Chemotherapy (CHEMOT) El? APY), Volume 34, S
-2, pp. 134-149, 1986].

[Means for Solving the Problems] As a result of intensive research to solve the above problems, the present inventors found that T-2588 or an acid addition salt thereof and 2
The present invention has been completed based on the discovery that an oral cephalosporin composition containing an organic acid having 2 to 6 carbon atoms with a maximum double weight exhibits absorption equivalent to that after a meal even when fasting.

The oral cephalosporin composition of the present invention is extremely useful and can be expected to be effective even for seriously ill patients who are unable to take meals.

The present invention will be explained in detail below.

The acid addition salt of T-2588 can be used without particular limitation as long as it is a pharmaceutically acceptable salt; for example, salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, malon Examples include salts with carboxylic acids such as malic acid, tartaric acid, and citric acid, and salts with sulfonic acids such as methanesulfone L D-toluenesulfonic acid and mesitylenesulfonic acid.

As the organic acid having 2 to 6 carbon atoms, any organic acid that can be used as a medicine can be used without particular limitation, such as fumaric acid, maleic acid, malonic acid, succinic acid, and glutaric acid. , dicarboxylic acids such as adipic acid; oxycarboxylic acids such as nigericolic acid, gluconic acid, tartaric acid, malic acid, citric acid; amino acids such as aspartic acid, glutamic acid; erythorbic acid and ascorbic acid, etc., especially ascorbic acid, erythorbic acid is preferred.

When the organic acid having 2 to 6 carbon atoms has a basic group, it may be used in the form of its acid addition salt.

Moreover, isomers such as optical isomers, racemic isomers, and geometric isomers may exist in organic acids having 2 to 6 carbon atoms, and all of them are included in the present invention.

The amount of organic acid having 2 to 6 carbon atoms is usually T-2588.
or more than twice the weight, preferably 2 times the weight of the acid addition salt thereof.
~3 times the weight.

Moreover, two or more kinds of organic acids having 2 to 6 carbon atoms can be used in combination.

The present invention relates to T-2588 or an acid addition salt thereof and carbon atoms having 2 to 2 carbon atoms.
This can be carried out by uniformly mixing 6 organic acids.

The oral cephalosporin composition of the present invention is used in the form of a tablet, capsule, granule, emulsion, fine granule, powder, or syrup, which are commonly known for oral administration. During formulation, commonly used additives such as excipients, surfactants, fillers, disintegrants, lubricants, and binders can be added as appropriate.

Furthermore, the administration method, dosage and frequency of administration of the oral cephalosporin composition of the present invention can be appropriately selected depending on the symptoms of the patient.
-2525 conversion '100~b.

[Effect of the invention] T-2525 in urine for 0 to 8 hours when the oral cephalosporin compositions of Example 1.2 and Reference Example 1.2 were orally administered to humans during fasting and 30 minutes after meals. The recovery rate is shown in Table-1.

Quantification method: High performance liquid chromatography (HPLC) method Column: Nucleosil (Nucleosi 1) 10C
IB [manufactured by Chemco] Measurement wavelength: 254 nm Mobile phase: 1 molar acetic acid-sodium acetate buffer (pH 5>
100d and a solution made by adding water to 100d and acetonitrile to make 1000d. It shows good absorption regardless of whether it is taken after meals.

[Example] Next, the present invention will be explained by giving examples and reference examples.
The present invention is not limited to this.

Example 1 10 g of T-2588 hydrochloride, 20 g of erythorbic acid, and 2 g of Koliton CL [manufactured by BASF] were mixed uniformly, and this was tableted to 1 g per tablet (238 mg potency as T-2525). do.

Example 2 10 g of T-2588 hydrochloride, 30 g of erythorbic acid, and 2 g of Koliton CL are mixed uniformly, and the mixture is compressed into 1q tablets (181 mg potency as T-2525).

Example 3 T-2588 hydrochloride 10g, erythorbic acid 20g,
Crystalline cellulose 48, Koliton CL 2g, light anhydrous silicic acid 0.329 and magnesium stearate 0.32g
Mix uniformly and slug tablet according to the conventional method. The obtained slug tablets were crushed and sieved through a 24-mesh screen, and then 1 g of Koliton CL and 0.32 g of magnesium stearate were added and mixed to give 470 m/tablet.
! j (1 oomy titer as T-2525) kJT tablets.

Example 4 T-2588/hydrochloride 109, ascorbic acid 3071
5 g of crystalline cellulose, 1 g of Koliton CL and 0.5 g of magnesium stearate are mixed uniformly and slug tableted according to a conventional method. The obtained slug tablets were crushed and
After sieving through mesh screen, Koliton CL1 g
and magnesium stearate 0. ! M was added and mixed to give 630 mg per tablet (100 mg as T-2525).
Compress into tablets (I1g titer).

Example 5 109 pieces of HCl-2588 hydrochloride, 23 parts of crystalline cellulose, and 27 parts of corn starch are mixed, and an appropriate amount of water is added to perform wet granulation. On the other hand, 20 g of Kuq-ene M, 2 g of crystalline cellulose, and Kotton CL1
Add an appropriate amount of water to g and perform wet granulation. These are dried, sized, and then mixed. To this, 1 tablet of magnesium stearate was added and mixed, and 943 IIig (T) was added per tablet.
-200m as 2525! 1 titer).

Example 6 T-2588 hydrochloride 10y and erythorbic acid 20g
are mixed uniformly, 3 g of hydrogenated soybean oil melted at 75°C is added thereto, and the mixture is kneaded while heating at 60°C to 70°C.

After cooling the mixture to the lowest temperature, it is pulverized to form a powder.

Example 7 109% of T-2588 hydrochloride, 209% of tartaric acid, 5g of crystalline cellulose, 1g of talc and 0.59% of magnesium stearate were mixed uniformly and then compressed using a compression granulator. After crushing the compressed product and sizing it with a 24-mesh screen, each capsule contains 478 mg (No. 0 capsule).
and fill it with capsules.

Example 8 10 g of T-2588 hydrochloride, 209 ascorbic acid and 10 y of lactose were mixed uniformly, hydrogenated soybean oil 39 melted at 75°C was added thereto, and heated at 60°C to 70'C. Practice. After cooling the mixture to the lowest temperature, it is crushed,
Collect powder with particle size between 32 mesh and 100 mesh. Add 33 g of 80 mesh granule monosaccharide to this to make fine granules.

Example 9 T-2588 hydrochloride 13.1!7, citric acid 26.2
9. Mannitol 57.79, sodium carboxymethylcellulose 2g and saccharin sodium 13 are uniformly mixed to form a dry syrup. (T- per 1q
Example 10 10 g of T-2588 hydrochloride, 20 g of fumaric acid, and Kotton CL [manufactured by BASF (8ASF>) 23 were uniformly mixed, and this was added to 1 tablet per tablet (23 Bm as T-2525).
Compress the tablets to y force 1i).

11 Example 11 T-2588 @ acid salt 10g, glutamic acid hydrochloride 2
0 g and Koliton CL29 are mixed uniformly and compressed into 1 tablet per tablet (238 m'j titer as T-2525).

Reference example 1 T-25881249, lactose 11g, crystalline cellulose 8
g, carboxymethylcellulose calcium 10g and corn starch 38.57g, and 4%
Wet granulation is performed by adding 75 d of hydroxypropyl methylcellulose aqueous solution. After drying, pulverize and sieve through a 24-mesh screen, add 47 g of carboxymethyl cellulose calcium and 1.5 g of magnesium stearate, and give 200 ay per tablet (100 ay as T-2525).
my titer). A film liquid consisting of 509 hydroxypropyl methylcellulose, 3 g of polyethylene glycol, 7 g of titanium chloride, and 5709 purified water was added to the obtained tablets in a conventional manner to give 6 mg per tablet.
Coating is performed to make film-coated tablets.

Reference example 2 T-2588/hydrochloride 140g, crystalline cellulose 10g
and corn starch 399 were mixed, and wet granulation was performed using 10% Coliton 30 (manufactured by BASF Corporation) at 50 degrees centigrade. After drying, it was crushed and sieved through a 24-mesh screen to obtain Neecy Diai Tsuru [Ac-Di-3ol (manufactured by Asahi Kasei Corporation)] 309 and magnesium stearate 63.
and compress into tablets at 230#Ig ('100rn9 titer as T-2525) per tablet.

Reference Example 3 108% of T-2588 hydrochloride, 109% of ascorbic acid, and 2g of Koliton CL were mixed uniformly, and 10% of this was added per tablet.
g (345 Ing titer as T-2525).

Reference Example 4 10 g of T-2588 hydrochloride, 159 g of erythorbic acid and 2 g of Koliton CL were mixed uniformly, and the mixture was compressed into 1q tablets (2H0 mg titer as T-2525).

Claims (1)

[Claims] Pivaloyloxymethyl 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[(5-methyl-2H-tetrazol-2-yl)methyl]-3-cephem -4-carboxylate or its acid addition salt and more than twice the weight of this with 2 or more carbon atoms
An oral cephalosporin composition containing 6 organic acids.