JP2003300885A - Antibacterial pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cefditoren pivoxil preparation as an antibacterial pharmaceutical composition safely administrable to patients and further improved in absorption via the digestive tracts by not only improving the wettability of cefditoren pivoxil but also maintaining highly oral-absorbable noncrystalline particles in a liquid for a long time. <P>SOLUTION: This pharmaceutical composition comprises cefditoren pivoxil, a sucrose fatty acid ester, optionally at least one pharmaceutically acceptable polymer, and further optionally at least one pharmaceutically acceptable additive. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antibacterial pharmaceutical composition having improved oral absorption, and more particularly to an antibacterial pharmaceutical composition containing cefditoren pivoxil.

[0002]

2. Description of the Related Art Cefditole which is an antibacterial compound
itoren) is formula (A):

[Chemical 1] Is a cephem compound. Its chemical name is
(+)-(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z) -2- (4-methyl) Thiazol-5-yl) ethenyl] -8-oxo-5-thia-1
-Azabicyclo [4.2.0] oct-2-ene-2-
It is a carboxylic acid. This compound is Japanese Patent Publication No. 3-64503
No. 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl]-. It is described by the chemical name of 3-cephem-4-carboxylic acid (syn isomer, cis isomer).

For the purpose of enhancing the gastrointestinal absorptivity of this cephem compound upon oral administration (hereinafter sometimes simply referred to as "oral absorptivity" in this sense), the 2-position carboxylic acid group of the cephem compound is a phenyl group. The pivaloyloxymethyl ester of cefditoren esterified with a baroyloxymethyl group is cefditoren pivoxil.
en Pivoxil) called. This prodrug compound is
Formula (B):

[Chemical 2] And its chemical name is (-)-(6R, 7R) -7.
-[(Z) -2- (2-aminothiazol-4-yl)
2-Methoxyiminoacetamide] -3-[(Z)-
2- (4-methylthiazol-5-yl) ethenyl]-
8-oxo-5-thia-1-azabicyclo [4.2.
0] Oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester. It is generally believed that this ester compound may exhibit higher oral absorbability than the original drug in the acid form. However, esterification of cefditoren did not necessarily result in a satisfactory or enhanced oral absorption.

In order to improve the oral absorbability of cefditoren pivoxil, a preparation has been proposed in which cyclodextrin or hydroxypropylcellulose, which is a water-soluble cellulose polymer derivative, is mixed with cefditoren pivoxil (Japanese Patent Publication No. 6-78234). (Patent Document 2) and Japanese Patent Laid-Open No. 7-17866 (Patent Document 3)). However, the addition of cyclodextrin to cefditoren pivoxil significantly enhances the bitterness derived from cefditoren pivoxil, and the formulation of tablets or granules obtained by the addition of hydroxypropylcellulose becomes bulky and difficult to take. There was a problem.

In order to solve these problems, a formulation in which a water-soluble casein salt is mixed with cefditoren pivoxil has been proposed in recent years (Japanese Patent No. 2831135 (Patent Document 4)). However, since casein is a protein derived from milk, it cannot be administered to patients with milk allergy.

[0006] As described above, there has been a demand for a preparation which allows safe administration of cefditoren pivoxil to a patient and ensures sufficient oral absorbability to expect its drug effect.

Further, Japanese Patent No. 3413406 (Patent Document 5) discloses a crystallographically stable amorphous cephalosporin composition and a method for producing the same, and the cephalosporin is made amorphous. Is disclosed to improve the oral absorbability. In addition, JP-A-2001-131
Japanese Patent Publication No. 071 (Patent Document 6) discloses a method for producing amorphous cefditoren pivoxil, and discloses that oral absorptivity is improved by amorphizing cefditoren pivoxil. Furthermore, WO02 / 87588
Japanese Patent Publication (Patent Document 7) discloses a method of producing an amorphous composition by mixing cefditoren pivoxil crystals with an organic polymer and pulverizing the crystals.

[0008]

[Patent Document 1] Japanese Patent Publication No. 3-64503

[Patent Document 2] Japanese Patent Publication No. 6-78234

[Patent Document 3] JP-A-7-17866

[Patent Document 4] Japanese Patent No. 2831135

[Patent Document 5] Japanese Patent No. 3413406

[Patent Document 6] Japanese Patent Laid-Open No. 2001-131071

[Patent Document 7] WO 02/87588

[0009]

However, since amorphous cefditoren pivoxil is liable to change into crystals in a solution, there is still room for improvement in antibacterial pharmaceutical compositions containing amorphous cefditoren pivoxil. Can be said.

That is, the present invention not only improves the wettability of cefditoren pivoxil, which can be safely administered to a patient, but also maintains a highly orally absorbable amorphous substance in a liquid for a long time. It is an object of the present invention to provide a cefditoren pivoxil preparation with improved absorption from the digestive tract.

[0011]

The present inventors have now found that crystallization of amorphous cefditoren pivoxil is suppressed in a preparation prepared by mixing cefditoren pivoxil and sucrose fatty acid ester. The present inventors have also confirmed that a solid composition comprising cefditoren pivoxil and sucrose fatty acid ester has excellent absorbability and immediate effect.

That is, the present invention provides a pharmaceutical composition comprising cefditoren pivoxil and sucrose fatty acid ester.

The pharmaceutical composition according to the present invention is advantageous in that the amorphous state of cefditoren pivoxil can be maintained for a long period of time, and that cefditoren pivoxil is excellent in oral absorption and immediate effect. Since the pharmaceutical composition according to the present invention is also excellent in wettability, it can be expected to have high dispersibility and dissolution in an aqueous solution.

[0014]

DETAILED DESCRIPTION OF THE INVENTION

The cefditoren pivoxil used in the present invention may be commercially available one or may be one produced according to a known method. Cefditoren pivoxil can be produced according to the method described in JP-B-3-64503. Further, an amorphous cefditoren pivoxil composition produced by coprecipitating cefditoren pivoxil and a water-soluble polymer can be used. In such manufacturing, the patent No. 341
Reference can be made to Japanese Patent No. 3406.

The sucrose fatty acid ester added to the pharmaceutical composition according to the present invention can be selected from commercially available ones.

The type of sucrose fatty acid ester is not particularly limited as long as it is pharmaceutically acceptable and extends the amorphous period of cefditoren pivoxil.
A hydrophilic one having a high HLB value is preferable, for example, HL
B value of 10 or more, preferably HLB value of 11 to 2
0 can be used. The HLB value can be calculated according to “Standard Oil and Fat Analysis Test Method” (1971) edited by Japan Oil Chemists' Society. One type of sucrose fatty acid ester can be used, or two or more types can be mixed and used as necessary.

The content of sucrose fatty acid ester is 0.1 with respect to 100 mg of cefditoren pivoxil.
~ 100 mg, preferably 0.1-5
mg.

The pharmaceutical composition according to the invention is preferably
It may further contain a pharmaceutically acceptable polymer. By adding a pharmaceutically acceptable polymer together with sucrose fatty acid ester to cefditoren pivoxil, the amorphous retention period of cefditoren pivoxil can be significantly extended.

The pharmaceutically acceptable polymer which can be added to the pharmaceutical composition according to the present invention can be selected from commercially available products.

The type of the polymer is not particularly limited as long as it does not inhibit the extension of the amorphous maintenance period of cefditoren pivoxil or it further extends the amorphous maintenance period, but is preferably pharmaceutically acceptable. Water-soluble polymers can be used.

Polymers that can be used include hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC), hydroxyethyl cellulose (HEC),
Examples thereof include polyvinylpyrrolidone (PVP) and hydroxypropyl cellulose (HPC), preferably HPM.
C, MC, and HEC. The polymer may be used alone or in combination of two or more as required.

The amount of the polymer added to cefditoren pivoxil can be 1 to 100 mg, preferably 1 to 50 mg based on 100 mg of cefditoren pivoxil.

The pharmaceutical composition according to the present invention can be formulated into various dosage forms suitable for oral administration as a drug. Suitable formulations for oral administration include powders, fine granules, granules,
Examples include tablets and capsules. Formulations suitable for oral administration include excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives, flavoring agents. It can be produced by a conventional method using one or more commonly used pharmaceutically acceptable additives such as an agent, a soothing agent and a stabilizer.

Although the content of cefditoren pivoxil in the pharmaceutical composition varies depending on the dosage form, it can be 5 to 90% by weight, preferably 10 to 80% by weight in the total composition. The dose for the treatment and prevention of bacterial infections and the like is appropriately determined in consideration of the usage, age, sex of the patient, degree of symptoms, etc., but is usually about 300 to 800 mg per adult per day. This can be administered once or several times a day.

[0026]

The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

In the examples, an amorphous cefditoren pivoxil composition produced by coprecipitating cefditoren pivoxil and a water-soluble polymer according to Japanese Patent No. 3413406 was used.

Reference Examples 1 to 5 and Examples 1 to 5 The amorphous cefditoren pivoxil composition and the surfactant were mixed at the compounding ratios shown in Table 1 to obtain a uniform powder mixture.

[0029]

[Table 1] Test Example 1 Amorphous cefditoren Pivoxil suspension concentration was 10 mg
/ ML, and a suspension was prepared by adding each additive so that the composition ratio shown in Table 1 was obtained. Specifically, water 350m
An aqueous solution prepared by dissolving each surfactant in L or 350 mL of water was added to 3.5 g of an equivalent amount of amorphous cefditoren pivoxil to give a suspension. The prepared suspension was evaluated for the amorphous retention period.

The amorphous maintaining period was measured as follows. That is, the suspension was stored under the condition of 25 ° C. (airtightness) and sampled immediately after preparation 1, 2, 3, 5, 7, 10, 14 days. The sampled suspension was centrifuged, and the residue dried under reduced pressure was subjected to powder X-ray diffraction measurement. The results are shown in Table 2.

[0031]

[Table 2] Crystallization of amorphous cefditoren pivoxil was promoted by surfactants other than sucrose fatty acid fatty acid ester, whereas the amorphous retention period was extended by sucrose fatty acid ester.

Examples 6 to 13 Amorphous cefditoren pivoxil composition, a surfactant and a polymer were mixed at the compounding ratios shown in Table 3 to obtain a uniform powder mixture.

[0033]

[Table 3] Test Example 2 Amorphous cefditoren Pivoxil suspension concentration 10 mg
/ ML, and a suspension was prepared by adding each additive so that the composition ratio shown in Table 3 was obtained. Specifically, water 350m
Sucrose fatty acid ester (DK ester SS) and each polymer were dissolved in L, and this aqueous solution was added to 3.5 g of an equivalent amount of amorphous cefditoren pivoxil to give a suspension. The prepared suspension was evaluated for the amorphous retention period.

The amorphous period was measured as follows. That is, the suspension was stored under the condition of 25 ° C. (airtightness) and sampled immediately after preparation 1, 2, 3, 5, 7, 10, 14 days. The sampled suspension was centrifuged, and the residue dried under reduced pressure was subjected to powder X-ray diffraction measurement. The results are shown in Table 4.

[0035]

[Table 4] The addition of only 0.1 mg of sucrose fatty acid ester was found to prolong the amorphous period. Further, it was confirmed that the addition of each polymer further extended the amorphous period.

Reference Examples 6 and 7 and Example 14 Tablets were produced at the compounding ratios shown in Table 5. The binder in Reference Example 6, the hydroxypropylmethylcellulose in Reference Example 7, and the sucrose fatty acid ester and hydroxypropylmethylcellulose in Example 14 were each dissolved in purified water to obtain a binding solution. Then, an appropriate amount of the above binding solution was added to the powder mixture of the remaining components, wet granulation was performed by a conventional method, and then purified water was distilled off to obtain granules. 200 mg of the granules were compression-molded to obtain tablets having flat sides.

[0037]

[Table 5] Test Example 3 The wettability of the tablets obtained in Reference Examples 6 and 7 and Example 14 was evaluated. 10 μL of water was added dropwise to the obtained tablets, and the time until the water droplets were completely absorbed in the tablets was measured. The results are shown in Table 6.

[0038]

[Table 6] Compared with the tablet containing sodium caseinate and sucrose fatty acid ester (Reference Example 7), the tablet containing sodium casein (Reference Example 6) had a faster water penetration time. Furthermore, the tablets containing sucrose fatty acid ester (Example 14) had a significantly shorter water penetration time than the tablets containing sodium caseinate. It has been found that the composition according to the invention improves wettability significantly over conventional wettability improving methods.

Continued front page    F term (reference) 4C076 AA29 BB01 CC34 CC42 DD68                       EE16 EE32 FF01 FF34                 4C086 AA01 AA02 CC12 CC17 MA03                       MA05 MA43 MA52 NA05 NA11                       NA15 ZB35

Claims (6)

[Claims] 1. A pharmaceutical composition comprising cefditoren pivoxil and sucrose fatty acid ester. 2. Sucrose fatty acid ester is added in an amount of 0.1 to 100 per 100 mg of cefditoren pivoxil.
The pharmaceutical composition according to claim 1, which contains mg. 3. The pharmaceutical composition according to claim 1 or 2, further comprising a pharmaceutically acceptable polymer. 4. The pharmaceutical composition according to claim 3, wherein the polymer is one or more water-soluble polymers selected from hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, and hydroxypropylcellulose. object. 5. The polymer is cefditoren pivoxil 100.
The pharmaceutical composition according to claim 3 or 4, containing 1 to 100 mg per mg titer equivalent amount. 6. The pharmaceutical composition according to any one of claims 1 to 4, further comprising one or more pharmaceutically acceptable additives.