JP2002097131A - Tablet with improved elutability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet of ceftizoxime alapivoxil hydrochloride, having improved elutability and stability. SOLUTION: This tablet contains the ceftizoxime alapivoxil hydrochloride as an active ingredient, and further contains one or more kinds of succinic acid, ascorbic acid, erythorbic acid and benzethonium chloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a tablet having improved dissolution and stability of a drug, in particular, ceftizoxime arapivoxil hydrochloride, one of cephalosporins.

[0002]

BACKGROUND OF THE INVENTION Ceftizoxime arapivoxil hydrochloride is
Pivaloyloxymethyl-[(6R, 7R) -7-[(Z) -2- [2-
[(S) -alanylamino] -4-thiazoyl] -2-methoxyiminoacetamide] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-en-2-carboxylate]
Hydrochloride (Pivaloyloxymethyl-[(6R, 7R) -7-[(Z) -2- [2-
[(S) -alanylamino] -4-thiazolyl] -2-methoxyiminoaceta
mido] -8-oxo- 5-thia-1-azabicyclo [4,2,0] oct-2-ene-2
-carboxylate] hydrochloride. This compound has a broad antibacterial spectrum and excellent antibacterial activity. Particularly, ceftizoxime (CZX), which is an active substance having strong antibacterial activity and bactericidal activity against Gram-positive bacteria and Gram-negative bacteria, has an L-alanyl group and pi. It is a prodrug-type cephalosporin in which a valoyloxymethyl group is introduced to enhance gastrointestinal absorption and solubility to enable oral administration (Japanese Patent Publication No. 6-102667). The properties and production method of ceftizoxime arapivoxil hydrochloride are reported in JP-B-6-102667. This publication introduces various preparations and discloses combinations with organic acids such as citric acid. In addition, as a technique for improving the absorption and solubility of other cephalosporin compounds in the digestive tract, it has been reported to add an organic acid such as citric acid to a cephalosporin compound (see, for example, US Pat. JP-B-57-139015, JP-B-58-83696, JP-B-57-7418, etc.).

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide ceftizoxime arapivoxil hydrochloride tablets which are superior in stability and dissolution.

[0004]

Means for Solving the Problems The present inventors have studied to obtain tablets of ceftizoxime hydrochloride arapivoxil with excellent stability and dissolution properties. Tablets are generally widely used dosage forms, but have a problem that they are sometimes not sufficiently dissolved because they are strongly compressed during preparation, in which case, for example, disintegration that can be used as a pharmaceutical additive Although an agent and a dispersant are added, effective methods are different for each drug, and there is no effective method for all drugs.

[0005] When ceftizoxime arapivoxil hydrochloride is made into a tablet, a tablet in which the active ingredient is blended at a relatively high concentration is required. It was newly confirmed that the tablet was hardly disintegrated and had poor solubility even when a tablet was prepared by adding a disintegrant, probably because the properties were strongly affected. Therefore, as disclosed in the prior art, a tablet was prepared by adding citric acid, an organic acid, to ceftizoxime arapivoxil hydrochloride,
It was confirmed that the active ingredient was unstable and the residual activity and color tone were seriously deteriorated, and it was confirmed that the means for solving the problem was extremely complicated.

The present inventors have studied extensively in order to solve these problems, and when forming tablets containing ceftizoxime arapivoxil hydrochloride, succinic acid, ascorbic acid, erythorbic acid, or benzethonium chloride was used. It was confirmed that a tablet satisfying both solubility and stability was formed when any one of the above was used, and the present invention was completed.

That is, the present invention provides a tablet comprising ceftizoxime arapivoxil hydrochloride as an active ingredient and at least one of succinic acid, ascorbic acid, erythorbic acid and benzethonium chloride.

[0008] The present invention also relates to the above-mentioned tablet using the Japanese Pharmacopoeia, general test method, disintegration test method, second liquid, and the Japanese Pharmacopoeia, general test method, dissolution test method, second method (paddle method). The tablet wherein the dissolution rate of the active ingredient from the tablet after 60 minutes is 80% or more, and the residual rate of the active ingredient when the tablet is stored at 65 ° C. for 4 weeks is 90% or more Is desirable. Further, in the present invention, it is desirable that ceftizoxime arapivoxil hydrochloride be contained in the tablet in an amount of 70 W / W% or more from the viewpoint of pharmacological effects. Further, in the present invention, it is desirable that the addition amount of at least one of succinic acid, ascorbic acid, erythorbic acid, and benzethonium chloride is 0.05 part by weight or more based on 1 part by weight of ceftizoxime arapivoxil hydrochloride.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below. Ceftizoxime arapivoxil hydrochloride used in the tablet of the present invention is not particularly limited as long as it is a dry solid, but is preferably a powder having a fine particle diameter upon mixing. It does not matter whether it is amorphous or crystalline. The production method and efficacy are described in Japanese Patent Publication No. 6-102667, respiratory tract infection, gonococcal urethritis, obstetrics and gynecology, and therapeutic agents that can show high efficiency against infectious diseases. Become.

The tablet of the present invention contains ceftizoxime arapivoxil hydrochloride as an active ingredient as described above, and ceftizoxime arapivoxil hydrochloride is contained in the tablet, usually at 70 W / W%.
Or more, preferably 80 W / W% or more, particularly preferably 90 W / W%
It is preferable to include the above.

The tablet of the present invention contains at least one of succinic acid, ascorbic acid, erythorbic acid and benzethonium chloride. The amount of these carriers to be added is not particularly limited as long as the effects of the present invention are exerted, and when used in combination, it may be slightly before or after, for example, 1 part by weight of ceftizoxime hydrochloride arapivoxil. The carrier is usually 0.05 parts by weight or more, preferably,
0.1 parts by weight or more, more preferably 0.2 parts by weight or more. Also, the upper limit is not particularly limited,
If the amount of the carrier is too large, the tablet becomes large and it becomes difficult to take the tablet.
0.5 parts by weight or less, particularly preferably 0.3 parts by weight or less is exemplified.

In preparing the tablet of the present invention, other pharmaceutical additives (hereinafter, referred to as other carriers) may be used as long as the effects of the present invention are not impaired or the effects of the present invention are minimized. A) can be added. The other carrier is
It is used as a pharmaceutical excipient, and the type of the final tablet is not limited as long as it has the effects of the present invention exemplified below in the solubility and stability of ceftizoxime hydrochloride arapivoxil. In addition, by adjusting the amount of addition or reduction or increase, by selecting the formulation method,
One skilled in the art can select other carriers. Usually, those which do not interact with ceftizoxime hydrochloride arapivoxil over time are preferable, and it is preferable that the carrier is a powder carrier at normal temperature. For example, corn starch,
Preferred examples include lactose and magnesium stearate. In consideration of the above-mentioned convenience of administration, the amount of these excipients is, for example, 0.2 parts by weight or less, and preferably 0.1 parts by weight or less, based on 1 part by weight of ceftizoxime arapivoxil hydrochloride. You. The upper limit is not particularly limited, but if the amount of the carrier is too large, the tablet becomes large and it becomes difficult to take the tablet. Therefore, the upper limit is usually 0.5 part by weight or less.

As a method for preparing the tablet of the present invention, generally known methods can be employed, but ceftizoxime arapivoxil hydrochloride and the above-mentioned carrier, and if necessary, other appropriate carriers are added in an appropriate step. Examples of the method include mixing and directly tableting, or granulating as appropriate, followed by tableting to obtain tablets.
As the granulation method, any of a wet granulation method and a dry granulation method may be used, but it is usually preferable to use a dry granulation method. For example, a composition comprising ceftizoxime arapivoxil hydrochloride and succinic acid (for example, manufactured by Mitsubishi Chemical Corporation, trade name: succinic acid) is added with magnesium stearate (for example, trade name, manufactured by Taihei Chemical Industry, magnesium stearate). After compression-molding with a dry granulator (eg, Roller Compactor RC-156, manufactured by Freund Corporation), sieving, corn starch (eg, Shikishima, trade name, Shikishima starch), and magnesium stearate were added. The prepared powder can be tableted with a tableting machine (for example, C / P12, manufactured by Kikusui Seisakusho) to obtain the tablet of the present invention. Also, the size of the tablet
Although not particularly limited, usually, the diameter is about 7 to 9 mm, the thickness is about 2 to 4 mm, and the weight is about 1 in consideration of the convenience of taking.
A preferred size is 50 to 300 mg. Although the shape of the tablet is not particularly limited, it is preferable that the tablet has a columnar shape and a curvature surface.

These tablets may be coated, if necessary, with a film-coating base which is pharmaceutically acceptable and does not interfere with the effects of the present invention. The film coating base is desirably coated so that the total weight of the film coating base to be coated is 1 to 10%, preferably 2 to 5% based on the weight of one tablet of the present invention.

Ceftizoxime arapivoxil hydrochloride is effective in the form of powder in the form of water or acidic to weakly alkaline liquids, but gels when tablets are produced by conventional techniques. Thus, it was confirmed that the solubility was affected by the properties of the drug, often affecting the solubility, and it was particularly difficult to secure effective solubility with two Japanese Pharmacopoeia solutions. The tablet of the present invention is a tablet which has solved the above-mentioned problems, and in particular, has secured a liquid and effective solubility in a water or acidic to weakly alkaline region.

The dissolution of the tablet of the present invention in the Japanese Pharmacopoeia in 2 liquids is performed according to the Japanese Pharmacopoeia / General Test Method, Dissolution Test Method 2 (paddle method). The elution rate can be determined by the absorbance measurement method described in above. In other words, the disintegration test method 2
Using a liquid (pH 6.8), the elution rate in 60 minutes is preferably 80% or more, more preferably 90% or more, and 95 to 100%.
% Is particularly preferable.

The stability of the tablet of the present invention can be determined by a residual test (quantitative method) under severe conditions (65 ° C., 4 weeks) and visual inspection. That is,
The quantitative value and change in appearance (color change) after storing the tablets in the sealed standard bottle in a thermostat at 65 ° C. for 4 weeks are compared with the quantitative value and initial appearance at the start (initial). The initial quantitative value is 100% and the survival rate after 4 weeks is 90%
As described above, it is preferable that the change in appearance is extremely small or no change. Further, it is particularly preferable that the residual ratio is 95 to 100% and the change in appearance is extremely small or no change.

The tablet of the present invention is usually administered orally.
The dose varies depending on the age of the patient and the degree of symptoms, but usually 100 to 600 mg of ceftizoxime arapivoxil hydrochloride is administered as an active ingredient per day in one or several doses per adult. It is preferable that the tablet of the present invention contains ceftizoxime hydrochloride arapivoxil in an amount of usually 100 to 250 mg, preferably 150 to 200 mg.

[0019]

EXAMPLES The present invention will be specifically described based on test examples, examples, comparative examples, experimental examples and the like. However, the present invention is not limited to these examples. The ceftizoxime arapivoxil hydrochloride used in Examples and the like was
It was prepared according to the following method according to JP-A-6-102667.

<Synthesis of Ceftizoxime arapivoxil hydrochloride> 2- [N- (tert-butoxycarbonyl) -L-alanylaminothiazol-4-yl] -2- (syn) -methoxyiminoacetic acid A mixture of 199 g and 1.2 L of ethyl acetate was added to -5
Cooled to ° C. Methanesulfonyl chloride (56 mL) and triethylamine (120 mL) were added, and the mixture was stirred at 0 ° C for 15 minutes.
The reaction solution was added to a mixed solution of 102 g of 7-amino-3-cephem-4-carboxylic acid (manufactured by Otsuka Chemical Co., Ltd.), 347 mL of methanol, 102 mL of water and 155 mL of triethylamine, and further reacted at -10 ° C for 15 minutes. The mixture was extracted with 1 L of water, adjusted to pH 2.4 by adding 2 L of water and hydrochloric acid, and stirred at 10 ° C. for 30 minutes. The precipitate is collected by filtration, and 7β- {2-} 2- [N- (tert-butoxycarbonyl) -L-alanylaminothiazol-4-yl]}-2- (Z)
-249 g of methoxyiminoacetamide｝ -3-cephem-4-carboxylic acid were obtained. 7β- {2- {2- [N- (tert-butoxycarbonyl) -L-alanylaminothiazol-4-yl]}
-2- (Z) -Methoxyiminoacetamide｝ -3-cephem-4
-Carboxylic acid is N, N-dimethylacetamide 0.9L and water
Dissolve in 250 mL, pivaloyloxymethyl iodide
142 g and 50 g of diisopropylamine were added, and the mixture was stirred at 0 ° C. for 4 hours. 2.5 L of ethyl acetate was added, and the mixture was washed with 2.5 L of 1N-HCl, 2.5 L of 6% saline, 2.5 L of 2% aqueous sodium bicarbonate, 2.5 L of 6% saline, and 2.5 L of water.

The solvent was distilled off under reduced pressure, and acetonitrile 3.3 L
And the solvent is replaced with piperoyloxymethyl 7β- ｛2-
{2- [N- (tert-butoxycarbonyl) -L-alanylaminothiazol-4-yl]}-2- (Z) -methoxyiminoacetamido｝ -3-cephem-4-carboxylate in acetonitrile 500 mL (Net261g) was obtained. Piperoyloxymethyl 7β- {2-} 2- [N- (tert-butoxycarbonyl)
335 mL of hydrochloric acid was added to -L-alanylaminothiazol-4-yl] {-2- (Z) -methoxyiminoacetamido} -3-cephem-4-carboxylate, and the mixture was stirred at 5 ° C for 1 hour.
The solution was added to 6.8 L of isopropanol, 3.4 L of acetone and 0.3 L of water, and stirred at 0 ° C. for 2 hours. The precipitate was collected by filtration and pivaloyloxymethyl 7β- {2- [2- (L-alanylaminothiazol-4-yl)]-2- (Z) -methoxyiminoacetamido} -3-cephem- 166 g of powder of 4-carboxylate hydrochloride (ceftizoxime arapivoxil hydrochloride) was obtained.

[0022]

Example 1 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of succinic acid (manufactured by Mitsubishi Chemical), and 2 parts by weight of magnesium stearate (manufactured by Taihei Kagaku Sangyo) were weighed, and the mixture was homogenized by a chemical mill. After mixing, the mixture was compression-molded with a hydraulic hand press (manufactured by Shimadzu Corporation) to produce a tablet of 200 mg per tablet.

[0023]

Example 2 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of ascorbic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder. The subsequent method is described in Example 1.
In the same manner as described above, a tablet of 200 mg per tablet was produced.

[0024]

Example 3 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of erythorbic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder. The subsequent method is described in Example 1.
In the same manner as described above, a tablet of 200 mg per tablet was produced.

[0025]

Example 4 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of benzethonium chloride (manufactured by Wako Pure Chemical Industries),
Weigh 2 parts by weight of magnesium stearate,
Mix uniformly with a chemical grinder. The subsequent method was the same as in Example 1 to produce a tablet of 200 mg per tablet.

[0026]

Example 5 85 parts by weight of ceftizoxime hydrochloride arapivoxil, 13 parts by weight of succinic acid, and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder. The subsequent method was performed in the same manner as in Example 1, and one tablet 188 mg
Tablets. (Amount of succinic acid = 2/3 amount of Example 1)

[0027]

Example 6 91 parts by weight of ceftizoxime arapivoxil hydrochloride, 7 parts by weight of succinic acid, and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder. The subsequent method was performed in the same manner as in Example 1, and one tablet 176 mg
Tablets. (Amount of succinic acid = 1/3 of Example 1)

[0028]

Comparative Example 1 98 parts by weight of ceftizoxime arapivoxil hydrochloride and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder. After that,
In the same manner as in Example 1, a tablet of 200 mg per tablet was produced.

[0029]

Comparative Example 2 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of citric acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder. The subsequent method was the same as in Example 1 to produce a tablet of 200 mg per tablet.

[0030]

[Comparative Example 3] 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of carmellose (manufactured by Gotoku Yakuhin, trade name, NS-300) and 2 parts by weight of magnesium stearate were weighed, and the mixture was homogenized with a chemical grinder. Mix. The subsequent method was the same as in Example 1 to produce a tablet of 200 mg per tablet.

[0031]

Comparative Example 4 80 parts by weight of ceftizoxime arapivoxil hydrochloride, 18 parts by weight of sucrose fatty acid ester (manufactured by Mitsubishi Chemical Foods, trade name, Ryoto Sugar Ester P-1670), and 2 parts by weight of magnesium stearate were weighed. And mix uniformly with a chemical grinder. The subsequent method was the same as in Example 1 to produce a tablet of 200 mg per tablet.

[0032]

COMPARATIVE EXAMPLE 5 98 parts by weight of ceftizoxime arapivoxil hydrochloride and 2 parts by weight of magnesium stearate were weighed and uniformly mixed by a chemical grinder to obtain a mixed powder.

[0033]

[Test Example 1] <Japanese Pharmacopoeia, General Test Method, Dissolution Test Method 2 (Paddle Method)> A stirrer (paddle) is installed on the rotating shaft of a Japanese Pharmacopoeia two-liquid dissolution tester (Toyama Sangyo NTR-6100). Attach and put 900mL of Japanese Pharmacopoeia, General Test Method, Disintegration Test Method 2nd Liquid (JP2 Liquid) in the vessel,
Rotate the paddle at 50 rpm and keep at 37 ° C. Subject's tablet 1
The test is started by placing the tablets in a sinker (tubular mesh container) and in a vessel. At 5, 10, 15, 20, 30, and 60 minutes after the start of the test, 10 mL of the eluate was collected, and filtered using a membrane filter (0.45 μm 25P manufactured by Kurabo Industries) with a pore size of 0.8 μm or less. Measure exactly 1 mL of the next filtrate, add 2 mL of JP to make 10 mL, and use this solution as the sample solution. Separately, weigh accurately 50 mg of ceftizoxime arapivoxil hydrochloride, add water and dissolve to make exactly 50 mL, and weigh exactly 1 mL of this solution.
Add the solution to make exactly 50 mL, and use this solution as the standard solution. Perform a test on the sample solution and standard solution according to the Japanese Pharmacopoeia, General Test Methods, and Absorbance Measurement Method, and measure the absorbance at a wavelength of 272 nm to determine the dissolution rate. Test solution (2 liquids of JP): To 250 mL of 0.2 mol / L potassium dihydrogen phosphate TS, add 118 mL of 0.2 mol / L sodium hydroxide TS and water to make 1000 mL. The solution is clear and colorless and has a pH of about 6.8.

[0034]

[Test Example 2] <Residual test / visual inspection> Pack the bottle of the subject into the No. 2 standard bottle, close the inner stopper, close the cap,
After storing in a thermostat at 4 ° C for 4 weeks, a quantitative test (residual rate) and a visual appearance test were performed. Survival rate is 100% of initial value
The residual rate after 4 weeks is determined by the following quantitative method. The appearance is
Visually confirm the color change.

<Quantitative method (HPLC method)> 25 mg of ceftizoxime arapivoxil hydrochloride was weighed and the mobile phase was added to make up to 50 mL. Similarly, the tablet of the subject was mortar-pulverized, and the equivalent amount of ceftizoxime arapivoxil hydrochloride 25 mgW was equivalent. Weigh in and add mobile phase to 50 mL
And a 0.45 μm membrane filter (Millipore)
Millex R-HV 25mm) to make a sample solution. With 10 μL of each sample and standard solution, the peak area of ceftizoxime hydrochloride arapivoxil is measured by the HPLC method.

The measurement conditions are as follows. Detector: UV spectrophotometer (measurement wavelength: 254 nm) Column: A stainless steel tube with an inner diameter of about 6 mm and a length of about 15 cm
Pack μm octadecylsilylated silica gel. Mobile phase: methanol in 560 mL of 0.5 M phosphate buffer (pH 3.0)
Add 220 mL and 220 mL of acetonitrile. Flow rate: 1.0m
L / min Column temperature: room temperature

[0037]

[Test Example 3] <Japanese Pharmacopoeia, General Test Method, Dissolution Test Method 2 (Paddle Method)> Japanese Pharmacopoeia 1 Liquid or Water Dissolution Tester (Toyama Sangyo NTR-6100) Attach a paddle), put 900 mL of the first liquid (or water) of the Japanese Pharmacopoeia, General Tests and Disintegration Test Method into the vessel, rotate the paddle at 50 rotations and keep it at 37 ° C. One test tablet is placed in a sinker (tubular mesh container) and placed in a vessel to start the test. At 5, 10, 15, 20, 30, 60 minutes after the start of the test, 10 mL of eluate was collected,
Membrane filter with pore size 0.8μm or less (Kurabo Industries)
Filter using 0.45 μm25P), remove 5 mL of the first filtrate, accurately measure 1 mL of the next filtrate, add 2 mL of JP to make 10 mL, and use this solution as the sample solution. Separately, weigh accurately 50 mg of ceftizoxime arapivoxil hydrochloride, add water to dissolve, and add exactly 50 mL
Measure exactly 1 mL of this solution, add 1 solution (or water) to JP to make exactly 50 mL, and use this solution as the standard solution. Perform a test on the sample solution and standard solution according to the Japanese Pharmacopoeia, General Test Methods, and Absorbance Measurement Method, and measure the absorbance at a wavelength of 272 nm to determine the dissolution rate. Test solution (1st JP solution): 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid
And water to make 1000 mL. The solution is clear and colorless and has a pH of about 1.2. Test liquid: water

[0038]

EXPERIMENTAL EXAMPLE 1 With respect to the tablets produced in Examples 1 to 6 and Comparative Examples 1 to 4 and the powder produced in Comparative Example 5, the dissolution test method of Test Example was carried out to determine the dissolution rate. Table 1 shows the results.
It was shown to.

[0039]

EXPERIMENTAL EXAMPLE 2 The tablets produced in Examples 1 to 6 and Comparative Examples 1 to 4 and the powder produced in Comparative Example 5 were stored in a thermostat at 65 ° C. for 4 weeks according to the method of Test Example 2. , The residual ratio and changes in appearance were confirmed. The results are shown in Table 1.

[0040]

[Table 1] <Coloring>-: No coloring (discoloration) ±: Neither can be said +: Coloring (discoloration) present <Judgment> ○: 60 minutes dissolution rate 80% or more Residual rate 90% or more
Coloring-± level ×: 60 minutes Elution rate less than 80% Residual rate less than 90%

[0041]

Experimental Example 3 The dissolution test method of Test Example 3 was carried out on the tablets produced in Examples 1 to 6 and Comparative Examples 1 to 4 and the powder produced in Comparative Example 5 to determine the dissolution rate. As a result, JP1
60% for all tablets and powder of Comparative Example 5 in liquid and water
The dissolution rate of 90 minutes to 100% can be ensured.
It was confirmed that there was no problem in dissolution.

As is clear from Table 1 (the results of Experimental Examples 1 and 2), the tablets of Examples 1 to 4 to which succinic acid was added, the tablets to which ascorbic acid was added, the tablets to which erythorbic acid was added, Tablets with added benzethonium
The elution rate of 60 minutes with 2 Japanese Pharmacopoeia is over 80% for both, 65 ℃,
The residual ratio after 4 weeks was 90% or more, and the appearance was such that the coloring could not be identified visually. As a result, these four types of carriers are highly effective in improving the dissolution property of ceftizoxim hydrochloride arapivoxil in two Japanese Pharmacopoeia by adding at least one type of carrier, and are stable over time without interaction. It can be said to be a preferred carrier. Example 5 in which the amount of succinic acid was changed,
The tablet of No. 6 also gave substantially the same results as the tablets of Examples 1-4. In Example 1, about 0.2 part by weight of succinic acid was added to 1 part by weight of ceftizoxime arapivoxil hydrochloride, but in Examples 5 and 6, it was about 0.14 and 0.07 part by weight. As is clear from the table, there is no difference in the dissolution rate, residual rate, and appearance due to the difference in the amount of succinic acid, so succinic acid was eluted even at about 0.1 part by weight per 1 part by weight of ceftizoxime hydrochloride It was confirmed that the effect of improving the properties was obtained.

It was confirmed that the tablet of Comparative Example 1 was excellent in both the residual ratio and the appearance, but hardly eluted with the Japanese Pharmacopoeia. In the case of the mixed powder of Comparative Example 5 having the same composition as that of Comparative Example 1, good results were also obtained in terms of the residual ratio, appearance, and dissolution properties. It was confirmed that effective solubility in the liquid could not be ensured. The citric acid tablets of Comparative Example 2 had an effective dissolution rate, but had a low residual rate and coloring, and were hardly effective at least in this usage method and amount. In the tablet containing carmellose (often used as a disintegrant) of Comparative Example 3, the residual ratio and appearance were good, but the dissolution rate was extremely low, like the tablet of Comparative Example 1, and the effect of improving dissolution was obtained. Was not obtained. In the tablet containing the sucrose fatty acid ester of Comparative Example 4 (often classified as a dispersant), the dissolution was slightly improved, but the effective dissolution rate could not be ensured, and the residual rate and appearance were also poor. No valid value was obtained.

From the results of Experimental Examples 1 to 3, at least one of succinic acid, ascorbic acid, erythorbic acid and benzethonium chloride was added to ceftizoxime arapivoxil hydrochloride, and other pharmaceutical additives which did not hinder their effects. It was confirmed that the tablets prepared by adding the compound ensured effective solubility in water and liquidity in an acidic to weakly alkaline region and were stable over time.

[0045]

According to the present invention, it is possible to provide a tablet having improved dissolution of ceftizoxime hydrochloride arapivoxil and improved stability.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 31/04 A61P 31/04 F term (Reference) 4C076 AA37 BB01 DD19 DD42 DD59 FF33 FF36 4C086 AA01 BC82 GA07 MA05 MA35 NA03 ZB35

Claims (4)

[Claims] 1. A tablet comprising ceftizoxime arapivoxil hydrochloride as an active ingredient and at least one of succinic acid, ascorbic acid, erythorbic acid and benzethonium chloride. 2. The Japanese Pharmacopoeia, general test method, disintegration test method,
In the Japanese Pharmacopoeia, General Test Method, Dissolution Test Method, and Second Method (Paddle Method) using the second liquid,
The dissolution rate after 60 minutes is 80% or more, and the tablet is
2. The tablet according to claim 1, wherein the residual ratio of the active ingredient when stored for 4 weeks is 90% or more. 3. The tablet according to claim 1, wherein the tablet contains ceftizoxime arapivoxil hydrochloride in an amount of 70 W / W% or more.
Or the tablet according to 2. 4. The method according to claim 1, wherein the amount of at least one of succinic acid, ascorbic acid, erythorbic acid and benzethonium chloride is at least 0.05 part by weight based on 1 part by weight of ceftizoxime arapivoxil hydrochloride. Item 1
3. The tablet according to any one of 3.