JPH092953A - Valfloxacin formulation - Google Patents

Abstract

(57) [Summary] [Structure] A valfloxacin preparation characterized by containing low-substituted hydroxypropylcellulose and / or crospovidone. [Effect] The valfloxacin preparation of the present invention is a useful preparation that exhibits a relatively rapid dissolution property in the acidic to neutral range and is less susceptible to the disintegration / dissolution properties by pH.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to valfloxacin formulations. More specifically, without being affected by pH,
The present invention relates to a valfloxacin preparation characterized by containing low-substituted hydroxypropylcellulose and / or crospovidone, which exhibits rapid dissolution.

[0002]

2. Description of the Related Art Valfloxacin is disclosed, for example, in Japanese Patent Laid-Open No.
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4 described in Japanese Patent Publication No. 95177, etc.
A new quinolone-based synthetic antibacterial agent represented by -oxoquinoline-3-carboxylic acid.

Although the above-mentioned publication discloses a method for synthesizing valfloxacin, it does not describe any specific pharmaceutical formulation.

[0004]

New quinolone type synthetic antibacterial agents are widely used as oral antibacterial agents having good absorbability, broad antibacterial spectrum and strong antibacterial activity.
Since the single dose is relatively large at 100 to 200 mg, tablets are often selected from the viewpoint of ingestability. However, when formulated as tablets, disintegration due to pressure compression
It is necessary to design in consideration of the change in dissolution property, and a drug with a high content of the active ingredient is particularly susceptible to the active ingredient.

Valfloxacin is a structurally amphoteric compound and has a relatively high solubility at low pH but a high pH (pH 5).
Above), the solubility is low, for example, the solubility at pH 6.8 is as low as 1/173 of the solubility at pH 1.2. Therefore, in the case of tablets with a high content of the active ingredient, the disintegration / dissolution and absorption properties fluctuate depending on the pH in the digestive tract, making it difficult to ensure stable bioavailability.

As a result of intensive studies to solve these problems, the present inventor has completed the present invention by finding a valfloxacin preparation showing a relatively rapid dissolution property in the acidic to neutral range.

[0007]

Valfloxacin used in the present invention is 1-cyclopropyl-6-fluoro-
1,4-Dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3
A carboxylic acid, and its pharmaceutically acceptable salts, hydrates, esters, optical isomers and in vivo 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-Methylaminopiperidin-1-yl)
It also includes a prodrug that can be converted to 4-oxoquinoline-3-carboxylic acid.

Valfloxacin is disclosed, for example, in JP-A-3-9.
It is obtained by heating and drying, for example, vacuum drying the valfloxacin undried powder obtained by the method described in Japanese Patent No. 5177. It can also be obtained by using the methods described in JP-A-5-272121, JP-A-5-294938 and JP-A-6-9619.

The formulations according to the invention are obtained by adding to valfloxacin low-substituted hydroxypropylcellulose and / or crospovidone.

The low-substituted hydroxypropylcellulose of the preparation of the present invention has a hydroxypropoxyl group (-OC ₃ H
₆ OH) having a degree of substitution of 5.0 to 16.0% by weight, preferably a hydroxypropoxyl group substitution degree of 1
One of them is 0.0 to 13.0% by weight. Examples of such a low-substituted hydroxypropyl cellulose include LH-11, LH-21, LH-31 manufactured by Shin-Etsu Chemical Co., Ltd., and the like.

The concentration of the low-substituted hydroxypropylcellulose and / or crospovidone added to the valfloxacin formulation is, for example, in the case of tablets, the low-substituted hydroxypropylcellulose is 2.5% or more per 100-200 mg of valfloxacin or Crospovidone is preferably 2.5% or more, preferably low-substituted hydroxypropylcellulose 5% or more or crospovidone 5% or more. When both low-substituted hydroxypropyl cellulose and crospovidone are added, the concentration of both should be 2.5% or more, preferably 5% or more.

The low-substituted hydroxypropyl cellulose and / or crospovidone is granulated together with valfloxacin, for example, by kneading / granulating / adding a binder solution containing hydroxypropyl cellulose, corn starch and the like.
It may be dried, or may be added and mixed later to the granulated powder.

In the present invention, in addition to low-substituted hydroxypropyl cellulose and / or crospovidone, lactose,
Excipients such as sucrose, mannitol, and crystalline cellulose, conventional flavors, colorants, and the like may be added as appropriate to formulate with valfloxacin. The preparation obtained in the present invention can be used as it is, but it can be further formulated into tablets, pills, fine granules, granules, capsules, powders and the like by adding necessary additives.

The present invention will be described in more detail with reference to the following examples. The present invention is not limited to these examples.

【Example】

[0015]

[Formulation Example 1] Tablets, fine granules and capsules were produced from the following ingredients in accordance with ordinary formulation techniques.

[0016]

[0017]

[0018]

[0019]

Example 1 With respect to 200 mg of valfloxacin, low-substituted hydroxypropyl cellulose (L
-HPC LH31, manufactured by Shin-Etsu Chemical Co., Ltd., crospovidone (Kolidone CL, manufactured by BASF), hydroxypropyl starch (HPS101, manufactured by Freund) and partially pregelatinized starch (PCS, manufactured by Asahi Kasei) at 10 mg. Lactose 65.5 mg as a forming agent, crystalline cellulose (Avicel PH101 manufactured by Asahi Kasei) 20 mg, and hydroxypropyl cellulose (HPC) as a binder.
-L, manufactured by Nippon Soda Co., Ltd.) at a ratio of 4.5 mg, water was added, and the mixture was kneaded in a mortar. After drying, the particles were sieved through a 20 mesh sieve, the tablet diameter was φ10 mm, and the tablet weight was 300 mg /
Tablets were obtained by static pressure molding at a molding pressure of 1000 kg to obtain tablets. Separately, tablets in which the disintegrant was replaced with lactose (disintegrator-free system)
Was made for comparison. The obtained tablets were measured with a hardness tester (Pharmatest Co., Ltd.) and a disintegration tester (Toyama Sangyo Co., Ltd.) (test liquid water and Japanese Pharmacopoeia No. 1 liquid-pH 1.
2) is shown in Table 1.

[0020]

[Table 1]

From Table 1, L-HPC or Kollidon CL
When using, the disintegration time was shortened for both water and the Japanese Pharmacopoeia No. 1 solution when no disintegrant was added, and when HPS or PCS was used, the disintegration time was prolonged for any of the test solutions.

[0022]

Example 2 L-HPC (LH-31) was added to 150 g of valfloxacin according to the formulation ratio of Formulation Example 1.
6 g, lactose 47.6 g as an excipient, crystalline cellulose 1
5g was added, and HPC-L 5% aqueous solution 54 was used as a binder.
g, and using a stirring granulator (manufactured by Powrex) while adding water, blade 500 rpm, cross screw 2
Granulated at 000 rpm. The obtained granulated product is granulated using a crushing granulator (made by Okada Seiko Co., Ltd.), and dried at 50 ° C. in a shelf dryer.
After drying for 3 hours, the particles were sieved through a 20 mesh sieve. To 147.3 g of the obtained granules, 1.5 g of hardened oil (Labrywax 101, manufactured by Freund) and 1.2 g of calcium stearate were added. The obtained blended powder was tableted with a single tableting machine (Okada Seiko Co., Ltd.) to give a tablet diameter of φ7.
Tableted under the conditions of 5 mm, tablet weight 150 mg / tablet, molding pressure 500 kg, valfloxacin 100 mg, L-HP
A formulation containing C2.5% was obtained.

Separately, L for 150 g of valfloxacin
-HPC (LH-31) 5.6 g, lactose 42 g, crystalline cellulose 15 g were added, and HPC-L 5% aqueous solution 54 g
Was added, and similarly granulated, dried and sized. L-HPC (LH-11) with respect to the obtained granulated product of 14.35 g
After compounding 3.75 g, hydrogenated oil 1.5 g and calcium stearate 1.2 g, tableting was performed in the same manner to obtain a preparation containing valfloxacin 100 mg and L-HPC 5%.

Further, valfloxacin 150 g, L-HPC (LH-31) 5.6 g, lactose 36.4 g,
Crystalline cellulose (15 g) was added, and HPC-L 5% aqueous solution (54 g) was added, and similarly granulated, dried and sized. For 139.8 g of the obtained granulated product, L-HPC (LH-
11) After compounding 7.5 g, hydrogenated oil 1.5 g, and calcium stearate 1.2 g, tableting was performed in the same manner to obtain a preparation containing valfloxacin 100 mg and L-HPC 7.5%.

About the obtained tablets, using an automatic dissolution tester (JASCO), the paddle method 900 m1, test liquid 3 types (p
H1.2: Japanese Pharmacopoeia No. 1 solution, pH 4.0: acetate buffer solution, pH 6.5: phosphate buffer solution) was subjected to an elution test. Table 2 shows the measurement results of the time at which 75% of valfloxacin in the preparation was eluted.

[0026]

[Table 2]

From Table 2, in the preparation containing valfloxacin 100 mg, the elution time at each pH was within 20 minutes by adding 2.5% of L-HPC to the preparation.
The drug product containing 5% or more of the compound had excellent dissolution properties, and the dissolution time at each pH was almost the same.

[0028]

Example 3 Valfloxacin 10 obtained in Example 2
The blended powder of the preparation containing 0 mg and 5% of L-HPC was tableted with a single punch tableting machine at a diameter of 9.5 mm and a weight of 300 m.
Tablets were obtained under the conditions of g / tablet and molding pressure of 750 kg to obtain a preparation containing 200 mg of valfloxacin and 5% of L-HPC. Separately, for 150 g of valfloxacin, L-HP
C (LH-31) 11.2 g, lactose 30.8 g, crystalline cellulose 15 g were added, and HPC-L 5% was used as a binder.
54 g of an aqueous solution was added, and granulation, drying and sizing were performed in the same manner as in Example 2. L- with respect to 139.8 g of the obtained granules
After compounding 7.5 g of HPC (LH-11), 1.5 g of hardened oil, and 1.2 g of calcium stearate, tableting was carried out in the same manner to obtain a preparation containing 200 mg of valfloxacin and 10% of L-HPC. For the tablets obtained, the measurement results of the time at which 75% of valfloxacin in the formulation was eluted were measured.
It is shown in the table.

[0029]

[Table 3]

From Table 3, in the preparation containing 200 mg of valfloxacin, the elution time at each pH was almost the same by adding 5% or 10% of L-HPC to the preparation.

[0031]

From the above results, the valfloxacin preparation obtained by the present invention has a high content of the main drug and is excellent in elution properties, and the elution times in the acidic to neutral regions are almost the same. Therefore, the change in bioavailability due to pH in the digestive tract can be reduced.

Claims (3)

[Claims] 1. A valfloxacin preparation containing low-substituted hydroxypropylcellulose and / or crospovidone. 2. The preparation according to claim 1, wherein the low-substituted hydroxypropyl cellulose has a hydroxypropoxyl group (—OC ₃ H ₆ OH) substitution degree of 5.0 to 16.0% by weight. 3. The preparation according to claim 1, wherein an excipient is further added in addition to the low-substituted hydroxypropyl cellulose and / or crospovidone.