JP2831135B2 - Antibacterial composition for oral administration - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an antibacterial composition for oral administration comprising a mixture of cefditoren pivoxil and a pharmaceutically acceptable water-soluble caseinate, which has a bitter taste upon oral administration. The present invention relates to a novel antibacterial composition for oral administration of cefditoren pivoxil, which is reduced or almost eliminated, is rapidly soluble in water and has high gastrointestinal absorption of the cefditoren component. The present invention also relates to an antibacterial composition for oral administration comprising a mixture of a pharmaceutically acceptable water-soluble polyphosphate of cefditoren pivoxil and a water-soluble caseinate, which has a bitter taste upon oral administration. The cefditoren pivoxil component in water is reduced or almost eliminated, is rapidly soluble in water, and has a high gastrointestinal absorption of the cefditoren component, and after storage of the composition at an elevated temperature. The present invention relates to a novel antibacterial composition for oral administration of cefditoren pivoxil, which can maintain a high dissolution rate.

Further, the present invention reduces the bitter taste of cefditoren pivoxil and comprises mixing cefditoren pivoxil with a pharmaceutically acceptable water-soluble caseinate, and reduces the dissolution rate of cefditoren pivoxil into water. Increasing methods are also included.

BACKGROUND ART Cefditoren has the following formula (A): Which has a chemical name of (+)-(6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(Z) -2- (4-methylthiazole-
5-yl) ethenyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid. This cephem compound has a common name of cefditoren and is described in Japanese Patent No. 1698887 (Japanese Patent Publication No. 3-64503), U.S. Pat. No. 4,839,350 and European Patent No. 0175610 as 7- [2- Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid (syn isomer, cis Isomers). For the purpose of enhancing the gastrointestinal absorption of the cephem compound during oral administration (hereinafter sometimes simply referred to as oral absorption), the carboxy group at the 2-position of the cephem compound is a pivaloyloxymethyl group. The pivaloyloxymethyl ester of cefditoren esterified with is a prodrug whose generic name is known as Cefditoren pivoxyl. This prodrug compound has the following formula (B): 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.

Pharmaceutical compounds, which are originally in the form of an acid (hereinafter sometimes simply referred to as drugs), have their acid groups esterified at the ester-forming group, and the resulting ester compound is esterified by esterification. Increased or increased solubility, thereby increasing the membrane permeability of the drug in the gastrointestinal tract, which allows the ester compound to increase gastrointestinal absorption compared to the original drug in acid form, i.e., enhanced It is generally believed that they can exhibit a controlled oral absorption. However, as is well known, the gastrointestinal absorption of a drug is closely related to the solubility of the drug in water. Esterified drugs have reduced fat properties as a result of their increased fat solubility, such as wetting to water and dispersibility in water. Therefore, the esterification of pharmaceutical compounds is a major problem because it cannot necessarily achieve a satisfactory degree of enhancement or improvement of gastrointestinal absorption.

Cefditoren pivoxil in ester form is a prodrug with a strong bitter taste that is unpleasant to those who receive oral administration, even though cefditoren itself, which is an antibacterial active substance, does not show bitterness when administered orally. Therefore, it is a major problem to reduce the bitterness of cefditoren pivoxil to an extent that oral administration of cefditoren pivoxil is acceptable to the patient. On the other hand, in order to solve a certain problem concerning the oral absorption of cefditoren pivoxil, a formulation in which cyclodextrin or a water-soluble cellulose-based polymer hydroxypropylcellulose is blended with cefditoren pivoxil has recently been proposed. (JP-A-1-268637 and JP-A-7-17866). However, the addition of cyclodextrin to cefditoren pivoxil causes the cyclodextrin to form a water-soluble complex with cefditoren pivoxil, which greatly increases the solubility of cefditoren pivoxil itself. Thus, the bitterness derived from this drug, cefditoren pivoxil, was greatly enhanced. For those who have been orally administered the above-mentioned formulation comprising a mixture of cefditoren pivoxil and cyclodextrin, the strong bitter taste of the drug enriched with the cyclodextrin formulation is a major hindrance.

In addition, in order to improve the oral absorption of cefditoren pivoxil by adding hydroxypropylcellulose, the usual amount of hydroxypropylcellulose used when used as a conventional binder (1 to the weight of the formulation).
% Added amount), it is necessary to increase the blending amount of hydroxypropylcellulose to an amount far exceeding the amount. When hydroxypropylcellulose is blended in such a large amount, the action of hydroxypropylcellulose acting as a binder is strongly exhibited.

In order to suppress the binding action of such a considerably large amount of compounded hydroxypropylcellulose, it is added to cefditoren pivoxil so as to maintain the disintegration of the prepared tablets or granules to an appropriate degree. It is necessary to considerably increase the amount of disintegrant added. This causes another problem that the resulting tablet or granule formulation becomes bulky and difficult to take.

Furthermore, by adding hydroxypropylcellulose to cefditoren pivoxil, it is difficult to remove water in a preparation comprising a mixture of cefditoren pivoxil and hydroxypropylcellulose, and it is not possible to minimize water in the preparation. There is also a problem that the stability of the drug component is likely to be reduced. In addition, the method of blending hydroxypropylcellulose with cefditoren pivoxil cannot sufficiently reduce the bitterness of cefditoren pivoxil itself to a satisfactory degree.

On the other hand, conventionally, various methods for masking or reducing the bitter taste of a pharmaceutical composition or preparation containing a drug having a bitter taste are generally known. For example, a method of coating the particle surface of a drug with a coat film is one of the known methods for masking bitterness. This method of coating the particle surface of the drug is suitable for tablet-type preparations, but when applied to preparations such as granules and fine granules, the surface becomes rough and unpalatable, and furthermore, the preparation process is However, there are drawbacks such as complexity of the system. A method of blending a sweetener or a flavor with a bitter drug is also used, but this method is not effective enough.

Thus, there is a current need for new and effective solutions to the problem of reducing or minimizing the bitter taste of bitter drugs to an acceptable level for the recipient.

DISCLOSURE OF THE INVENTIONThe present inventors contain cefditoren pivoxil as an active drug component, but do not show unpleasantly strong bitterness when administered orally, and have high absorption of the cefditoren component in the digestive tract,
That is, extensive research has been conducted to develop a novel orally administrable cefditoren pivoxil preparation having a high oral absorption of a cefditoren component. As a result of many of these studies, a formulation consisting of a mixture of cefditoren pivoxil and a fixed amount of a water-soluble caseinate has improved dispersibility of the formulation in water, thereby increasing the solubility of cefditoren pivoxil in water. Not only can a significant increase in the dissolution rate of the component be obtained, but also a significant increase in the dissolution concentration in water of the cefdiphthene pivoxil component, which can be obtained by elution from the formulation in water within a certain predetermined time. The inventors have found that this can be achieved. Therefore, a formulation consisting of a mixture of cefditoren pivoxil and a predetermined amount of a water-soluble caseinate, when this formulation is orally administered, the oral absorption of the cefditoren component compared to the oral administration of cefditoren pivoxil alone The inventors have also found that the properties can be increased.

The caseinate incorporated in the above-mentioned preparation comprising a mixture of cefditoren pivoxil and caseinate exhibits the property of forming casein micelles when placed in water. The formation of said micelles of casein in water can be obtained by increasing the dispersibility of the formulation in water, increasing the rate of dissolution of the cefditoren pivoxil component in water, and dissolving out of the formulation in water within a given time. In the above-mentioned points that can increase the dissolving concentration of the cefditoren pivoxil component in water and further reduce the bitterness of the cefditoren pivoxil component, it is considered that the cefditoren pivoxil component acts advantageously on the cefditoren pivoxil component. Has been estimated.

Furthermore, it has been found by the present inventors that the incorporation of a certain amount of a water-soluble caseinate, which is the above formulation, can greatly reduce or minimize the bitterness of cefditoren pivoxil itself. Based on these findings, the present invention described in detail below has been completed.

Therefore, in the first aspect of the present invention, the composition comprising a mixture of cefditoren pivoxil and a certain amount of a pharmaceutically acceptable water-soluble caseinate is characterized by having a reduced bitter taste, There is provided an antibacterial composition of cefditoren pivoxil for oral administration, wherein the dispersibility of the product in water is increased and the dissolution rate of the cefditoren pivoxil component in water is increased.

The caseinate used in the composition of the present invention may be any salt as long as it is a water-soluble caseinate, and is not limited to a particular type of caseinate. However, because of its high solubility in water, sodium caseinate
Alternatively, potassium caseinate (potassium caseinate) is preferred as the water-soluble caseinate. More preferably, using fresh skim milk powder as a raw material, the casein curd is separated and neutralized therefrom, and the casein sodium obtained by spray-drying the milk protein with reduced odor and color obtained thereby is used. It may contain the composition of the present invention. In addition, a very small amount to a small amount of casein itself may be mixed in the caseinate used in the composition of the present invention.

In the composition of the present invention, in order to clearly reduce bitterness, the amount of caseinate is preferably 0.1 part or more by weight per part of cefditoren pivoxil. However, the compositions of the present invention have a high dispersibility in water for formulations made from the compositions, and have a high dissolution rate in water of the cefditoren pivoxil component and within a predetermined time, for example, a predetermined time of 60 minutes. In order to increase the dissolution rate of the cefditoren pivoxil component obtained by eluting into the water from the present composition, the weight ratio of the cefditoren pivoxil and the caseinate blended in the present composition is as follows: It is preferably in the range from 1: 0.4 to 1: 4, particularly in the range from 1: 0.6 to 1: 2. here,
If the amount of caseinate incorporated in the composition is less than 0.1 part per 1 part of cefditoren pivoxil,
Such compositions do not provide the expected high dispersibility in water of the formulations made therefrom and do not provide the expected high dissolution rate of the drug component in water. On the other hand, if the amount of the caseinate incorporated in the composition exceeds the upper limit, that is, if the amount is more than 4 parts per part of cefditoren pivoxil, the preparation made from the composition becomes bulky. There is a problem that it becomes too difficult to take by oral administration. For these reasons, the weight ratio of cefditoren pivoxil to caseinate is from: 0.4 to 1:
It is desirable to be in the range of 4.

In producing an oral administration preparation from the composition of the present invention, the dosage form of the obtained preparation and the available production method are not particularly limited. For example, tablets from the composition of the present invention,
Oral preparations in the form of granules, dry syrups, powders, and capsules can be produced by a conventional method.

Further, for the purpose of improving the disintegration and dispersibility of a preparation made from the composition of the present invention, sucrose, lactose,
D-mannitol, potato starch, xylitol,
One or more excipients such as D-sorbitol and the like, and sodium carboxymethyl starch, crospovidone, croscarmetose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, The compositions of the present invention may additionally and preferably contain one or more disintegrants such as microcrystalline cellulose.
The amount of disintegrant added to the composition may be 0% by weight for the total composition of the oral dosage form made from the composition.
It should be in the range of ~ 45% by weight. Also, if necessary, the composition of the present invention may contain a pharmaceutically acceptable binder, a sweetener, a flavor, a lubricant, a preservative, a flavoring agent, a pharmaceutically acceptable additive such as a pigment. One or more may be added if desired.

Furthermore, the present inventors continued research on the storage stability of the antimicrobial composition according to the first present invention.

And, as a result, the present inventors have found that the first composition according to the present invention provides an elevated temperature for an extended period of time, e.g. When stored at an elevated temperature, not only the dissolution rate of the cefditoren pivoxil component in water from the composition after storage can be obtained, but also by elution from the composition after storage into water within a predetermined time. The concentration of the cefditoren pivoxil component in water was also greatly reduced as compared with the value that can be obtained with the composition of the present invention immediately after production, that is, the required components of the composition were cefditoren pivoxil and casein. The freshly prepared composition of the present invention is prepared by mixing a salt and optionally blendable additives, that is, an aqueous solution which can be obtained when the composition immediately after the preparation is placed in water. Compared to the values of the velocity and dissolution in water concentration, it was a very reduced.

The present inventors have further studied to solve this problem, and have succeeded in obtaining the knowledge described below.
That is, the present inventors have further found that, when the pharmaceutically acceptable water-soluble polyphosphate is added to the first composition of the present invention in a certain amount, the composition is added. Even when a composition comprising a water-soluble polyphosphate is stored at an elevated temperature of 40 ° C. for a period of three months, the composition after long-term storage at 40 ° C. is a component of cefditoren pivoxil from the composition. Dissolution rate in which water is eluted in water is not much lower than before storage, and the cefditoren pivoxil component can be obtained from the composition after storage by elution in water for a predetermined period of time. The concentration does not drop much.

Thus, in a second aspect of the present invention, it comprises a mixture of cefditoren pivoxil, an amount of a pharmaceutically acceptable water-soluble caseinate, and an amount of a pharmaceutically acceptable water-soluble polyphosphate. The composition is characterized by reduced bitterness, increased dispersibility in water of the composition, and increased dissolution rate of the cefditoren pivoxil component in water, and even after storage of the composition at an elevated temperature. There is provided an antibacterial composition of cefditoren pivoxil for oral administration which can maintain a high dissolution rate in water of a fuditoren pivoxil component.

In the composition according to the second invention, the caseinate incorporated is preferably sodium caseinate or potassium caseinate (potassium caseinate), as in the composition of the first invention. The compounding ratio (weight) of the cefditoren pivoxil component to the caseinate is preferably in the range of 1: 0.1 to 1: 4, and particularly preferably in the range of 1: 0.4 to 1: 2.

In a second composition according to the invention, the caseinate is present in such an amount that the compounding ratio (weight) of caseinate and polyphosphate is in the range from 1: 0.02 to 1: 0.06, in particular in the range from 1: 0.02 to 1: 0.05. And a water-soluble polyphosphate. With such a blending ratio, the desired good properties relating to the elution of the cefditoren pivoxil component from the stored composition to water even after long-term storage of the second composition of the present invention at an elevated temperature are obtained. It is certain that it can be demonstrated and maintained.

In other words, in other words, in the second composition of the present invention, the mixing ratio (weight) of caseinate and polyphosphate is 1: 0.
By adjusting the amount of polyphosphate in the composition to be in the range of 02 to 1: 0.06, the original high cefditoren pivoxil before storage, even after long-term storage of the composition at elevated temperature. The dissolution rate of the component in water and the high concentration of dissolution of the original cefditoren pivoxil component in water that can be obtained in a given time due to dissolution fall unduly lower than the rate and concentration obtained with the composition immediately after production. The second characteristic that can be prevented
Can be maintained in the composition of the present invention.

Most preferably, the water-soluble polyphosphate incorporated into the second composition of the present invention is pure sodium or potassium tripolyphosphate, but it may be commercially available sodium or potassium polyphosphate. Commercially available sodium or potassium polyphosphate usually contains sodium or potassium tripolyphosphate as a main component, and also contains trace amounts of sodium or potassium pyrophosphate, sodium or potassium trimetaphosphate and sodium or potassium highly condensed phosphate. It is.

In the second composition of the invention, the caseinate and the polyphosphate are:
When contained at a compounding ratio (weight) in the range of 0.02 to 1: 0.04, the disintegration of the composition is slightly improved as compared to the composition containing no polyphosphate. On the other hand, if the amount of the blended polyphosphate is more than the upper limit of 0.06 parts per part of the caseinate, the binding strength of the polyphosphate itself is unduly greatly increased. Compositions containing salts have reduced disintegration. Furthermore, the presence of the polyphosphate in the second composition of the present invention does not substantially adversely affect the action of the caseinate component that reduces the bitterness of the cefditoren pivoxil component. Was found.

The preparation of the second composition according to the invention can be carried out in a known manner, for example by simply mixing cefditoren pivoxil, caseinate, optional additives and polyphosphates to form a homogeneous powder mixture. . When the composition is to be manufactured as granules, mix cefditoren pivoxil with caseinate, add the aqueous polyphosphate solution to the powder mixture, and shape the resulting mixture into granules by a known wet granulation method. it can. The resulting granules can then be formed into tablets by conventional tableting methods. Alternatively, a uniform powder mixture consisting of the drug component, caseinate and optional additives is first prepared, which is then formed into granules by a known wet granulation method, and then the granules are dried and dried. It is also possible to spray a polyphosphate aqueous solution and finally dehydrate the granules.

The second inventive composition may, optionally, optionally comprise one or more of the same additives as described above for the first invention, such as disintegrants, excipients, lubricants and the like. Can be included.

Furthermore, as is evident from the description provided earlier in the first invention, the incorporation of cefditoren pivoxil with an aliquot of a pharmaceutically acceptable water-soluble caseinate allows the oral administration of this drug compound. It can reduce its bitterness to the extent that it is not uncomfortable at the time of administration, and can considerably improve the properties of the drug compound dissolved in water.

Therefore, in another aspect of the present invention, the weight ratio of cefditoren pivoxil to caseinate is in the range of 1: 0.4 to 1: 4,
Cefditoren pivoxil is mixed with a pharmaceutically acceptable water-soluble caseinate, preferably in the range of 1: 0.6 to 1: 2, thereby providing a homogeneous powder mixture of cefditoren pivoxil and caseinate. Reduce the bitterness of cefditoren pivoxil, increase the rate of dissolution of cefditoren pivoxil in water, and increase the concentration of cefditoren pivoxil in water that can be obtained by elution in water within a predetermined time. A method for increasing is provided.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the dissolution rate of cefditoren pivoxil from fine granules prepared from the composition obtained in Example 1 of the first present invention, and a similar case-free salt. It is a graph which shows the curve which shows the time-dependent transition of the change of the elution rate of cefditoren pivoxil from the comparative fine granule.

FIG. 2 shows the dissolution rate of cefditoren pivoxil from tablets prepared from the compositions obtained in Examples 1 to 8 of the first invention, and the casein salt prepared in Reference Example 2 was not included. It is a graph which shows the curve which changes with time of the change of the elution rate of cefditoren pivoxil from the tablet of a similar comparison.

FIG. 3 shows a beagle dog orally administered a tablet prepared in Example 4 of the first invention of the present invention or a similar comparative tablet produced in Reference Example 1 not according to the present invention. It is a graph which shows the curve which shows the time-dependent change of the change of the cefditoren concentration (microgram / ml) in the plasma samples which are collected from a dog.

FIG. 4 shows the dissolution rate of cefditoren pivoxil from the tablet prepared in Example 4 of the first invention,
About the dissolution rate of cefditoren pivoxil from the tablets produced in Example 10 of the present invention, immediately after the preparation of the test tablets, and at 40 ° C. of the test tablets, after storage for 3 months, cefditoren pivoxil of the tablets It is a graph which shows the curve which shows the transition of the change of the elution rate at the time of measuring an elution rate with time.

FIG. 5 shows the dissolution rate of cefditoren pivoxil from the tablet prepared in Example 4 of the first invention,
For the dissolution rate of cefditoren pivoxil from the tablets produced in Example 12 of the present invention, immediately after the production of the test tablets, and at 40 ° C. of the test tablets, after storage for 3 months Cefditoren pivoxil of the tablets 5 is a graph showing a curve representing a change over time in a change in the elution rate when the elution rate of the sample was measured.

BEST MODE FOR CARRYING OUT THE INVENTION Next, the first present invention is described in Examples 1 to 9 and Test Example 1 described later.
Examples 4 to 4 will be specifically described, but the present invention is not limited to these Examples and Test Examples.

Example 1 130 g of cefditoren pivoxil was added to sodium caseinate 52
A uniform powder mixture was prepared by mixing with 0 g, and an appropriate amount of purified water (prepared according to the Japanese Pharmacopoeia 13 revised edition) was added and kneaded. The kneaded mixture was granulated by a conventional wet granulation method to obtain fine granules. This fine granule is a powder that can be administered orally.

Examples 2 to 8 According to the component ratios, various powders of cefditoren pivoxil, sodium caseinate, D-mannitol and croscarmellol sodium were mixed according to the component ratios of the seven different composition formulations shown in Table 1 below. A homogeneous powder mixture was made.

An appropriate amount of water was added to the powder mixture and granulated by a conventional wet granulation method. The obtained granules were then added with magnesium stearate as a lubricant and compression-molded into tablets by a conventional method. As a result, the mixing ratio (weight) of cefditoren pivoxil and sodium caseinate is different for each formulation.
Tablets were prepared with seven formulations, 1: 0.1, 1: 0.2, 1: 0.4, 1: 0.6, 1: 0.8, 1: 1.0 and 1: 2.0. For each formulation, tablets of the same formulation were obtained on a 1000 tablet scale.

 The formulation of the manufactured tablets is detailed in Table 1 below.

Example 9 130 g of cefditoren pivoxil, sodium caseinate 39
A homogeneous powder mixture containing 0 g and 480 g of D-mannitol was prepared and granulated by a conventional wet method. Thus, granules having a composition containing each component in the following amounts per 1000 mg were produced.

Cefditoren pivoxil 130 mg Sodium caseinate 390 mg D-mannitol 480 mg Total 1000 mg Reference Example 1 A uniform powder mixture containing 130 g of cefditoren pivoxil, 130 g of β-cyclodextrin and 5 g of hydroxypropylmethylcellulose was prepared, and an appropriate amount of water was added thereto. Well kneaded. The obtained mixture was wet-granulated by a conventional method. Citric acid may degrade this drug compound if it comes into direct contact with cefditoren pivoxil, and due to incompatibilities, may have a different low substituted hydroxypropyl methylcellulose
A powder mixture was prepared by homogenizing 10 g and 150 g of citric acid, and this was combined with the granulated product. 6 g of magnesium stearate was further added to the obtained mixture, and the obtained mixture was tableted by a conventional method. As a result, a tablet having a composition containing each component in the following amounts per tablet (Comparative sample 1: see the prior art invention in JP-A-1-268637) was produced.

Cefditoren pivoxil 130 mg β-cyclodextrin 130 mg Hydroxypropyl methylcellulose 5 mg Low-substituted hydroxypropylmethylcellulose 10 mg
Citric acid 150 mg Magnesium stearate 6 mg Total 431 mg Reference example 2 Cefditoren pivoxil 130 g, D-mannitol 64 g
Further, a uniform powder mixture of croscarmellose sodium (95 g) was prepared, an appropriate amount of water was added thereto, and the mixture was granulated by a conventional wet method. Further, 3 g of magnesium stearate was added to the granules and mixed, and the mixture was tableted by a conventional method. As a result, a tablet (comparative sample 2) having a composition containing the components in the following amounts per tablet was produced.

Cefditoren pivoxil 130 mg D-mannitol 64 mg croscarmellose sodium 95 mg magnesium stearate 3 mg Total 292 mg Reference Example 3 A uniform powder mixture of cefditoren pivoxil 130 g and hydroxypropyl cellulose (type L) 390 g was prepared.
To this was added 3 kg of dichloromethane to dissolve. 480 g of D-mannitol was added to the obtained solution and suspended. The resulting suspension was heated with an evaporator to remove the induced solvent, and the residue was pulverized and sieved to collect particles having an appropriate particle size. Thus, a granule (comparative sample 3) having a composition containing the following components in the following amounts per 1000 mg was produced.

Cefditoren pivoxil 130 mg Hydroxypropyl cellulose 390 mg D-mannitol 480 mg Total 1000 mg Next, Test Examples 1 to 4 are shown for the first composition of the present invention, whereby the composition of the present invention is The dissolution rate in water is increased, the dissolution concentration in water of the drug component that can be obtained within a predetermined time by dissolution is also increased, and the oral absorption of the cefditoren component obtained in the composition of the present invention is high, and from the composition of the present invention, Test Example 1 Cefditoren pivoxil and sodium caseinate, further illustrating that the composition of cefditoren pivoxil according to the first invention possesses the advantageous properties of reduced bitterness of the prepared formulation. And 11 kinds of powders containing various mixing ratios, ie, the weight blending ratio of cefditoren pivoxil and sodium caseinate ( That is, A / B mixing ratio) is 1: 0.0, 1: 0.1, 1: 0.2: 1: 0.3,
Eleven kinds of powders of 1: 0.4, 1: 0.5, 1: 0.6, 1: 0.8, 1: 1, 1: 2 and 1: 4 were prepared by a wet granulation method according to Example 1. However, among the 11 kinds of powders prepared here, powders not containing sodium caseinate (A / B compounding ratio of 1: 0.0) are comparative samples outside the present invention.

Fill a cylindrical container with a hemispherical bottom with 100 ml of water,
At 7 ° C. in water 100 mg of cefditoren pivoxil was added with a considerable amount of one of these powders. While immediately stirring the water pool and the added powder in the container with a wing-shaped stirrer,
The concentration (mg / ml) of the drug (Cefditoren pivoxil) dissolved in the aqueous phase was measured over a period of 60 minutes from the addition of the powder. The dissolution rate (%) of the drug was calculated over time assuming that the dissolution rate of the drug when all of the drug was completely dissolved in water from the powder was 100%.

Specifically, the dissolution rate (%) of a drug eluted in water is
It was calculated by the following formula at each measurement.

Drug dissolution rate (%) = b / a × 100 where b represents the concentration of the drug dissolved in water (mg / ml) at each measurement, and a represents the total amount of the drug contained in the powder. It shows the theoretical maximum value (mg / ml) of the concentration of drug dissolved in water obtained when the drug is completely eluted in water.

 The test results obtained are shown in Table 2 below.

The numerical results of Table 2 are shown as a curve graph in FIG. 1 of the accompanying drawings, and this graph shows a curve showing the change over time in the dissolution rate (%) of the drug in water.

As can be seen from the curve in FIG. 1, the concentration of cefditoren pivoxil in water and the dissolution rate of the drug increased with an increase in the amount of sodium caseinate per part of the drug, and increased with cefditoren pivoxil. When the compounding ratio of sodium caseinate (that is, A / B ratio) was 1: 0.5 or more, the dissolution rate (%) of the drug reached an almost constant value.

In more detail, the following is found from the numerical values of the test results in Table 2. That is, for example, when the elapsed time is 5 minutes and 10 minutes, the sample No. 2
(A / B ratio = 1: 0.1) showed drug elution rates of 61.28% and 63.55%, but sample No.1 (comparative sample, A / B ratio = 1: 0.0) at the same measurement time point Drug dissolution rates of 53.31% and 58.15%
showed that. As can be seen, sample No. 2 according to the first invention can increase the drug dissolution rate by about 15% over the comparative sample No. 1 without sodium caseinate at the elapse of 5 minutes [ Formula: (61.28−53.31) /53.31×
Calculated from 100 = 14.9%], and at the time of 10 minutes elapsed time, the drug dissolution rate was about 9.3% higher than that of comparative sample No. 1.
[Calculation formula: (63.55−58.15) /58.15×100=
Calculated from about 9.3%]. Also, for example,
The sample No. 5 (A / B ratio = 1: 0.4) according to the first present invention was found to have a drug dissolution rate of 81.02% when measured for an elapsed time of 5 minutes. As described above, when the elapsed time is measured for 5 minutes, the drug dissolution rate of sample No. 5 can be increased by about 52% compared with comparative sample No. 1 [calculation formula: (81.02-53.31)
/53.51 x 100 = 51.96%.]

Test Example 2 Each product of the tablets produced in Examples 2 to 8 and Reference Example 2 was subjected to a dissolution test specified in the Japanese Pharmacopoeia (13 edition).
In this dissolution test, distilled purified water was used as the dissolution medium,
An apparatus comprising a cylindrical container having a paddle type stirrer and having a hemispherical bottom was used.

The aqueous phase of the purified water placed in the container was stirred with the stirrer, and the test tablets were placed in the aqueous phase. The dissolution rate (%) of the drug (Cefditoren pivoxil) eluted from the test tablet into water was evaluated over time over a period of 60 minutes immediately after the addition of the tablet to the aqueous phase.

The test was repeated three times, and the obtained progress was averaged and evaluated.

The obtained test results (as an average) are shown as a curve graph in FIG. 2 of the accompanying drawings, in which a curve showing the change (in minutes) over time of the dissolution rate (%) of the drug is shown.

The dissolution rate of each of the tablet products manufactured in Examples 2 to 8 and the tablet product manufactured in Reference Example 2 was 35.55%, 54.52%, 68.23%, 68.11%, at the time of measuring the elapsed time of 60 minutes. 68.8
The values were 4%, 67.98%, 67.56% and 21.82%.

As is clear from the curves in FIG. 2, the test tablets had a compounding ratio of cefditoren pivoxil and sodium caseinate of 1: 0.
When the value is 4 or more, it is recognized that the drug dissolution property of the tablet of the present invention is remarkably improved as compared with the comparative tablet containing no casein sodium, and that cefditoren pivoxil and sodium caseinate are used. Even when the compounding ratio is 1: 2, it is recognized that the effect of improving the dissolution properties of the drug is at the same level as above.

Test Example 3 This example was performed to test and demonstrate that the first composition of the present invention could have an excellent effect of improving the oral absorption of cefditoren drug. For this purpose, the gastrointestinal absorption of the cefditoren component was evaluated when a composition of the present invention was orally administered to a beagle dog as a test animal.

Test method: Each product of the tablets manufactured in Example 4 and Reference Examples 1 and 2 was used in this test. Body weight fasted after 16 hours 10
A female beagle dog weighing about 1 kg was treated with 1 tablet of water at a dose equivalent to 130 mg of cefditoren pivoxil per dog in water 3
Each was orally administered together with 0 ml.

After the administration, plasma samples were collected from the dogs every 0.25, 0.5, 1, 2, 4, 6, and 8 hours after the administration. The concentration of cefditoren (μg / ml) in the collected plasma sample was measured by a high-performance liquid chromatography method. The test was repeated five times, and the obtained result was evaluated as a mean value.

The obtained result test (as mean value)
The graph is shown as a curve graph, which shows a curve indicating that the concentration of Cefditoren (μg / ml) contained in the plasma sample changes with time (in hours).

As shown by the obtained test results, it is composed of a mixture of cefditoren pivoxil, caseinate sodium, D-mannitol, croscarmellose sodium, and the compounding ratio of cefditoren pivoxil and kazenin sodium is 1: 0.
In the tablet manufactured in Example 4 from the composition of the present invention, which is 4, a plasma sample collected at 1 hour after oral administration gave a cefditoren concentration value (mean value) of approximately 1.4 μg / ml, while In the comparative tablets manufactured in Reference Examples 1 and 2, the cefditoren concentration values (mean values) of approximately 1.15 μg / ml and 0.6 μg / ml, respectively, of the plasma samples collected one hour after their oral administration was gotten.

As can be seen from FIG. 3, the composition of Example 4 containing sodium caseinate according to the present invention has a clear increase in gastrointestinal absorption of the cefditoren component as compared with the comparative tablet of Reference Example 2 having a normal formulation. Can be given.

In addition, the obvious effect of increasing the oral absorbability of cefditoren obtained with the tablet of Example 4 was as described in JP-A-1-268637.
No., etc., the increase in cefditoren absorption obtained in the comparative tablet prepared in Reference Example 1 by mixing cefditoren pivoxil with β-cyclodextrin according to the known technique for promoting oral absorption of a drug. The effect is slightly better.

Furthermore, the amount of sodium caseinate added in the present invention is β
-Even if the addition amount of cyclodextrin is as low as half or less, the effect of increasing the oral absorbability of cefditoren obtained with sodium caseinate can be demonstrated to be equal to or more than the effect obtained with β-cyclodextrin. Is recognized.

For these reasons, a tablet formulation smaller than the tablet of Reference Example 1 and easy to take by oral administration can be produced by the present invention.

Test Example 4 In this example, a sensory test of the bitterness of the granules of Example 9 and the granules of Reference Example 3 was performed.

That is, 1 g of each of the test granules was given to each member (panelist) of the panel of examiners together with 5 ml of water, and 10 g
After containing it in the mouth for a second, the entire amount was exhaled, and the degree of bitterness at that time was evaluated on a three-point scale of "slightly bitter, bitter, very bitter", and a score of 1, 2, or 3 points was given in order.

In this test, 10 panelists were equally divided into 2 groups of 5 persons, and the first group of 5 panelists evaluated the bitterness of the granules of Example 9 and then carried out plenty of water in their mouth. After thorough rinsing, 30 minutes later, the bitterness of the other granule of Reference Example 3 was evaluated, and a second group of five panelists evaluated the bitterness of the granule of Reference Example 3 after the mouth was evaluated. Rinse thoroughly with plenty of water and adjust after 30 minutes to evaluate the bitterness of the other granules of Example 9.

The results obtained from the sensory tests are shown in Table 3 below. Reference Example 3
As compared to the bitterness of the granules of Example 9, the granules of Example 9 made from the composition of the present invention were found to have reduced bitterness.

Further, in order to demonstrate that the composition according to the second invention can maintain a high dissolution rate of the drug of the composition after storage at elevated temperature, the second invention is described in Examples 10 to 12 below.
And Test Examples 5 to 6 will be specifically described.

Examples 10 to 12 Cefditoren pivoxil, sodium caseinate, D-mannitol and croscarmellose sodium were used in the same proportions as shown in Example 4 above, and the mixing ratio of cefditoren pivoxil and kazenin sodium was
A homogeneous powder mixture of 1: 0.4 was prepared. An aqueous solution containing 0.007% (by weight) of commercially available sodium polyphosphate (containing sodium tripolyphosphate as a main component) was added thereto. In this case, the added amount of the aqueous solution of sodium polyphosphate is 1 mg or 2 mg per tablet of the finally produced tablet.
Alternatively, the amount was adjusted so that 3 mg of sodium polyphosphate was contained.

The mixture obtained by adding an aqueous solution of sodium polyphosphate to the above powder mixture was then subjected to wet granulation in the same manner as in Example 4. Magnesium stearate was further added to the obtained granules, and formed into tablets in the same manner as in Example 4. As a result, the mixing ratio of sodium caseinate and sodium polyphosphate was 1: 0.02, 1: 0.04 and 1:
Three tablets, 0.06, were produced according to the second invention on a scale of 1000 tablets.

Reference Examples 4 to 5 Cefditoren pivoxil, sodium caseinate, D-mannitol and croscarmellose sodium having the same component ratio as shown in Example 4 and the compounding ratio (weight) of cefditoren pivoxil to sodium caseinate was 1 :
A homogeneous powder mixture of 0.4 was prepared as in Examples 10-12.

The obtained powder mixture was mixed with a commercially available sodium polyphosphate (containing sodium tripolyphosphate as a main component) in an amount of 0.1%.
An aqueous solution containing 007% (by weight) was added. In this case, the amount of the aqueous solution of sodium polyphosphate added was such that 5 mg or 20 mg of sodium polyphosphate was contained per tablet of the finally obtained tablet.

The mixture obtained by adding an aqueous solution of sodium polyphosphate to the powder mixture was subjected to wet granulation in the same manner as in Example 4. Magnesium stearate was further added to the obtained granules, and formed into tablets in the same manner as in Example 4.
As a result, two kinds of tablets having a compounding ratio of sodium caseinate and sodium polyphosphate of 1: 0.1 and 1: 0.4, respectively, were manufactured on a scale of 1000 tablets.

Test Example 5 The tablets of Example 4 according to the first invention and the tablets of Examples 10 and 12 according to the second invention were prepared in accordance with the Japanese Pharmacopoeia (13 edition) immediately after the production of each tablet. The dissolution rate (%) of the drug component (cefditoren pivoxil) from these tablets to water was measured by a test method of a dissolution test. After storing these tablets in a closed container at 40 ° C. for 3 months, the tablets after storage were tested by the same test method as the above-mentioned dissolution test.

The test method of this dissolution test is to use a device consisting of a cylindrical container having a hemispherical bottom and equipped with a paddle-type stirrer.
The pool of water at 37 ° C. was stirred with a stirrer rotating at 0 rpm and the concentration of the drug in water was measured with the passage of time (in minutes). The dissolution rate of the drug in water (%) was measured in the same manner as in Test Example 1 described above. To calculate

The test was repeated three times, and the obtained test results were expressed as a mean value and a standard deviation. The results obtained are shown in Table 4 below.

The test results in Table 4 are shown as curve graphs in FIGS. 4 and 5 of the accompanying drawings, in which the dissolution rate (%) of the drug in the tablets of each test sample changes with time (in minutes). A curve indicating that the

As is clear from the curves in FIGS. 4 and 5, the tablet of Example 4 containing no sodium polyphosphate was obtained at 40 ° C., 3
After storage under severe conditions for months, it can be seen that the average value of the drug dissolution rate of the tablets has decreased considerably. In contrast, the tablets of Examples 10 and 12, each containing 1 mg and 3 mg of sodium polyphosphate per tablet, were treated at 40 ° C, 3
It can be seen that the drug dissolution rate of the tablet was prevented from substantially decreasing even after storage for months.

Test Example 6 Tablets of Example 4 and Examples 10 to 12 and Reference Example 4
Tablets Nos. To 5 were tested for disintegration properties of tablets by the disintegration test method specified in the Japanese Pharmacopoeia (13th revised edition). The tablets to be tested were placed in water at 37 ° C and the first solution of the disintegration test of the Japanese Pharmacopoeia (13th revised edition) (ie, artificial gastric juice, pH 1.2 shown in the Japanese Pharmacopoeia). When placed at 37 ° C., the disintegration of tablets was measured separately.

The disintegration of tablets is determined by placing 6 tablets in a water medium or pool of the first liquid of the disintegration test, then stirring by up and down movement and in a liquid medium until no visible solid particles are found in the liquid medium. The time (min) required for the tablet to disintegrate and completely disperse was measured and evaluated.

The test results obtained were evaluated as mean values and are shown in Table 5 below.

As can be seen from the test results in Table 5, the tablets of Examples 10 and 11 have better disintegration than the tablet of Example 4, but the tablet of Example 12 has a lower disintegration than the tablet of Example 4. Has been substantially reduced. Furthermore, the tablets of Reference Examples 4 to 5 in which the compounding ratio of sodium caseinate and sodium polyphosphate was compounded with sodium polyphosphate at a high value of 1: 0.1 or 1: 0.4 had higher disintegration than the tablet of Example 4. Significant reduction is observed.

INDUSTRIAL APPLICABILITY As described above in the first and second aspects of the present invention, the composition of the present invention has reduced bitterness, increased solubility of cefditoren pivoxil, and oral absorption of cefditoren This is advantageous in that it can provide a cefditoren pivoxil preparation for oral administration that is easy to take.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/42 A61K 47/42 L 9/14 M (72) Inventor Tomoko Murakami 2-195 Todehoncho, Saiwai-ku, Kawasaki-shi, Kanagawa Address Meiji Seika No. 1 Baikaso 105 No. 105 (72) Inventor Toshiyasu Gikouji 760 Shioka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Meiji Seika Co., Ltd. Pharmaceutical Research Institute (58) Field surveyed (Int.Cl. ⁶ , DB name) ) A61K 31/545 A61K 9 / 14,9 / 20 A61K 47 / 42,47 / 34 CA (STN)

Claims (13)

(57) [Claims] 1. A composition comprising a mixture of cefditoren pivoxil and an amount of a pharmaceutically acceptable water-soluble caseinate, wherein the composition has reduced bitterness and dispersibility of the composition in water. An antibacterial composition of cefditoren pivoxil for oral administration, wherein the cefditoren pivoxil component has an increased dissolution rate in water. 2. The composition according to claim 1, wherein the caseinate is sodium or potassium caseinate. 3. The compounding ratio (weight) of cefditoren pivoxil to caseinate is in the range of 1: 0.1 to 1: 4, especially 1: 0.4 to 1: 2.
2. The composition according to claim 1, wherein 4. The composition according to claim 1, further comprising one or more additives selected from pharmaceutically acceptable excipients and disintegrants. 5. The composition according to claim 1, which is formulated in the form of granules, fine granules or tablets. 6. A composition comprising a mixture of cefditoren pivoxil, an amount of a pharmaceutically acceptable water-soluble caseinate, and an amount of a pharmaceutically acceptable water-soluble polyphosphate. Characterized by reduced bitterness,
For oral administration, the dispersibility of the composition in water is increased and the dissolution rate of the cefditoren pivoxil component in water is increased, and the dissolution rate of the cefditoren pivoxil component in water can be kept high even after storage of the composition at an elevated temperature. An antibacterial composition of cefditoren pivoxil. 7. The composition according to claim 6, wherein the caseinate is sodium or potassium caseinate and the polyphosphate is sodium or potassium polyphosphate. 8. The composition according to claim 7, wherein the sodium or potassium polyphosphate is pure sodium or potassium tripolyphosphate or a commercially available sodium or potassium polyphosphate. 9. The compounding ratio (weight) of caseinate and polyphosphate is in the range of 1: 0.02 to 1: 0.06, especially 1: 0.02 to 1: 0.05.
7. The composition according to claim 6, wherein 10. The composition according to claim 6, wherein the compounding ratio (weight) of cefditoren pivoxil and caseinate is in the range of 1: 0.1 to 1: 4. 11. The method according to claim 1, further comprising one or more additives selected from pharmaceutically acceptable excipients and disintegrants, and formulated in the form of granules, fine granules or tablets. 7. The composition according to 6. 12. The pharmaceutical composition of cefditoren pivoxil such that the weight ratio of cefditoren pivoxil to caseinate is in the range of 1: 0.4 to 1: 4, preferably in the range of 1: 0.6 to 1: 2. Reducing the bitter taste of cefditoren pivoxil and dissolving cefditoren pivoxil in water, consisting of mixing with an acceptable water-soluble caseinate, thereby forming a homogeneous powder mixture of cefditoren pivoxil and caseinate A method for increasing the dissolution concentration of cefditoren pivoxil in water, which can be obtained by increasing the rate and eluting in water within a predetermined time. 13. The method according to claim 12, wherein the caseinate is sodium caseinate or potassium caseinate.