JPS63165321A - Cephalosporin composition for oral administration - Google Patents

Abstract

PURPOSE:To provide the titled composition containing T-2588 and an amino acid hydrochloride or a betaine hydrochloride and exhibiting nearly the same absorbability in starved state as well as after meal. CONSTITUTION:The objective composition contains (A) pivaloyloxymethyl 7beta-[(z)-2-( 2-aminothiazol-4-yl )-2-methoxyiminoacetamido]-3-[(5-methyl-2H-tetra zol-2-yl)methyl]-3-cephem-4-carboxylate (T-2588) having broad antibacterial spectrum against Gram-positive bacteria and Gram-negative bacteria and (B)>=0.8 pt.wt., preferably 1.0-1.5pts.wt. (based on 1pt.wt. of T-2588) of hydrochloride of an amino acid (e.g. glycine, glutamic acid, etc.) or hydrochloride of betaine. The composition is expected to be effective even to a grave patient who cannot take a food and has extremely high utility.

Description

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

More specifically, pivaloyloxymethyl 7β-[(Z
) -2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamide]-3-[(5-methyl-
2-tetrazol-2-yl)methyl]-3-cephem-4-carboxylate (hereinafter referred to as T-2588) or its acid addition salt and amino acid salt 11! The present invention relates to a cephalosporin composition for intravenous use containing a salt or betaine hydrochloride.

[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 metabolized by enzymes in the body, resulting in the corresponding free carboxylic acid compound, i.e., 7β. -[(Z) -2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[(5-methyl-2d-tetrazol-2-yl)methyl]-3-cephem- 4-carboxylic acid (hereinafter referred to as T-2525) is produced.

This T-2525 is an extremely excellent compound with a broad antibacterial spectrum against Durum-positive and Durum-negative bacteria (Japanese Patent Publication No. 52755/1983);
No oral cephalosporin compositions containing 8 or its acid addition salt and the hydrochloride of an amino acid or the hydrochloride of betaine are 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 (CHE), Volume 34, S
-2, pp. 134-149, 1986].

Means for Solving Problem E] As a result of intensive research to solve the above problems, the present inventors found that a solution containing T-2588 or its acid addition salt and an amino acid hydrochloride or a betaine hydrochloride. The present invention was completed based on the discovery that an oral cephalosporin composition exhibits almost the same absorption during fasting as after a meal.

The 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, @acid, nitric acid, and phosphoric acid; Examples include salts with carboxylic acids such as malonic acid, malic acid, tartaric acid, and citric acid, and salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and mesitylenesulfonic acid.

Amino acids in the amino acid hydrochloride include neutral or acidic amino acids such as glycine, cysteine, glutamic acid, and asparagine rIX1.

Examples of the betaine salt i1 include glycine betaine hydrochloride.

The amount of amino acid hydrochloride or betaine hydrochloride is as follows:
Usually 0.8 for T-2588 or its acid addition salt
A double weight or more, particularly between 1.0 and 1.5 times the weight, is preferable.

The composition of the present invention can be obtained by uniformly mixing T-2588 or an acid addition salt thereof with an amino acid hydrochloride or a betaine hydrochloride.

The composition of the present invention is used after being formulated into dosage forms commonly known for oral administration, such as tablets, capsules, granules, coarse granules, fine granules, powders, or syrups. During formulation, commonly used additives such as excipients, surfactants, fillers, disintegrants, lubricants, and binders can be added as appropriate.

Further, the administration method, dosage and frequency of administration of the composition of the present invention can be appropriately selected depending on the patient's symptoms, and for adults it is usually administered orally to a dose of 100 to
1200η/day may be administered in one to several divided doses.

[Effects of the Invention] Next, the urinary recovery rate of the composition of the present invention after oral administration will be shown.

1. Urinary recovery rate 0 of T-2525 when the compositions of the present invention of Examples 1 and 2 and the oral cephalosporin compositions of Reference Examples 1 and 2 were orally administered to humans during fasting and 30 minutes after meals. ~8
Table 1 shows the urinary recovery rate over time.

Quantification method: High performance liquid chromatography (HPLC) method Column: Nucleozil (NljCIeO3! 1) 10
CIB [manufactured by Chemco] Measurement wavelength: 254 nm Mobile phase: 1 molar acetic acid-sodium acetate buffer (pH 5>
100ml and 100ml of acetonitrile were added with water to make 100011Ij2 (the following is a blank space) As is clear from Table 1, the composition of the present invention exhibits good absorption regardless of whether fasting or after eating.

[Examples] Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 T-2588 hydrochloride 26.39, L-glutamic acid hydrochloride 26.3 g, Koliton CL [manufactured by BASF Co., Ltd. 12.0 g, Avicel PH102 (manufactured by Asahi Kasei Co., Ltd. >6.0 g).
44 g of Adsolider 101 (anhydrous silicic acid, manufactured by Freund), 2.0 g of stearin rlio, 6cj, and 1.29 g of magnesium stearate were mixed and slug tableted according to a conventional method. Crush the obtained slug tablets,
After passing through a 4-mesh screen, Koliton OL2
．． 09, Adsolida-1014,09 and magnesium stearate 1.2g, 720my per tablet
(200 m'j titer as T-2525).

Example 2 T-2588 @ acid @ 26.3 g, L-glutamate r! 1m39.4g, D! , J-ton CL2.2g, Avicel PH1026, 58g, Ad Solider 101 3.
0.6g of stearic acid, 0.66g of stearic acid, and 1.32y of magnesium stearate are mixed and slug tableted according to a conventional method. The obtained slug tablets were crushed and sieved through a 24-mesh screen, and then 58 g of Koliton CL2.29, Adsolida-1016, and 1.32 g of magnesium stearate were added to give one tablet of 896 ffiff (T-25
25 (200 m'j titer).

Reference example 1 T-2588124g, lactose 11g, crystalline cellulose 8
9. Carboxymethyl cellulose calcium 38, 59
75 d of a 4% hydroxypropyl methyl cellulose aqueous solution is added to the mixture and wet granulation is performed. After drying, pulverize and sieve through a 24-mesh screen, add 1.5 g of carboxymethylcellulose calcium, and make 200ff1g (T-25
25'+oomy titer). The resulting tablets contained 50g of hydroxypropyl methylcellulose, 39g of polyethylene glycol 6000, and 7g of titanium oxide.
Using a film liquid consisting of purified water 5709 and purified water, each tablet is coated to a thickness of 6 my by a conventional method to obtain a film coating.

Reference example 2 T-2588/hydrochloride 140g, crystalline cellulose 109
and corn starch 399 are mixed, and wet granulation is performed using 50 m of a 10% Koliton 30 (manufactured by BASF Corporation) aqueous solution. After drying, it was crushed and sieved through a 24 mesh screen to obtain Nishi Dear Tsuru [AC-[)i-So
l (Asahi Kaseisha!'ri) 303 and magnesium stearate 69, 230m per tablet!? (T-2
525 as 100. 'Fl! Compress into tablets (g titer).

Claims (1)

[Claims] Pivaloyloxymethyl 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[(5-methyl-2H-tetrazol-2-yl)methyl] - An oral cephalosporin composition containing 3-cephem-4-carboxylate or an acid addition salt thereof and an amino acid hydrochloride or betaine hydrochloride.