JPH04305526A - Medicinal composition - Google Patents

Abstract

PURPOSE:To obtain a readily administrable medicinal composition, capable of enhancing the solubility of a medicine, improving bioavailability and excellent in productivity in a composition of 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6- oxo-5-pyrimidinecarboxylic acid for oral administration. CONSTITUTION:A medicinal composition is characterized in that 1,6- dihydro-2-{2-(2-methyl propoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid as an active ingredient, a hydrophilic polymer as a binder and crosslinked sodium carboxymethyl cellulose as a disintegrating agent are used. The use of the aforementioned active ingredient finely divided to particles having <=10mum average particle diameter and 2-10m<2>/g specific surface area is effective in improving bioavailability. The ratio of the hydrophilic polymer used as the binder is preferably 0.2-2wt.% based on the weight of the above-mentioned active ingredient.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to pharmaceutical compositions, and more particularly, to pharmaceutical compositions containing 1,6-dihydro-2-{
The present invention relates to a preparation for oral administration containing 2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid.

0002

[Prior Art] 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid was disclosed as a novel compound having antiallergic effect in JP-A-60-100559. Also as JP-A-62
-267229 discloses its general tablets, granules, and soft capsules as an anti-peptic ulcer drug.

[0003] 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid is extremely difficult to dissolve in water, and has not been used in conventional oral preparations, especially tablets. Most of it is excreted in feces, and its bioavailability is extremely low. Therefore, in order to obtain a desired pharmacological effect, it is necessary to administer a large amount, which not only increases the cost, but also makes it impossible to manufacture small tablets that are easy to take.

[0004] Conventionally, methods such as amorphization and complexation have been proposed as pharmaceutical means to improve such problems. However, a problem with amorphization is that it requires the use of an organic solvent. That is, organic solvents not only pose a risk of fire or explosion during the process, but also there is a concern that the organic solvents remaining in the formulation may have an adverse effect on the human body. There is also a method of mixing and pulverizing the drug and carrier as a method that does not use organic solvents, but it is necessary to pulverize for a long time to ensure sufficient bioavailability.
In addition, there are other problems, such as requiring several times the amount of carrier than the drug. In complex formation, since a large amount of a polymer compound is used to form the complex, a long time is required for drying and pulverizing the complex, and therefore it cannot be said to be a method with excellent productivity.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems of the prior art, and is directed to the production of 1,6-dihydro-2-{2-(2-methylpropoxy)anilino } Regarding oral preparations containing -6-oxo-5-pyrimidinecarboxylic acid, the bioavailability can be improved, the manufacturing process is relatively simple, the manufacturing cost can be reduced, and oral administration is easy to take. The objective is to provide a formulation.

[0006]

[Means for Solving the Problems] The present inventors have discovered that 1,6-
Dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid has low bioavailability in its powder form but high bioavailability in suspension. Because the above compounds have large contact angles and exhibit significant water repellency, it takes a long time for them to become suspended in the gastrointestinal tract, which is one of the causes of reduced bioavailability. It was estimated that More specifically, 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid tends to aggregate in the gastrointestinal tract and cannot be sufficiently dispersed or suspended. It is thought that only a low bioavailability can be obtained because it passes directly through the absorption site.

[0007] The present invention was completed as a result of further research based on the above considerations.
- An oral preparation of {2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, characterized by using a hydrophilic polymer as a binder and cross-linked sodium carboxymethyl cellulose as a disintegrant. A pharmaceutical composition.

[0008] In the powder of 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, the average particle diameter is 10 μm or less and the specific surface area is 2 m2/g. It is effective to use fine particles of ~10 m2/g in improving the bioavailability.

Hydrophilic polymers used as binders in the pharmaceutical composition of the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, pullulan, and polyvinyl alcohol. Regarding the usage ratio of hydrophilic polymer, 1,6-dihydro-2-{2-(2-
Preferably, from 0.3 to 2% by weight, based on the weight of the methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, is used.

The pharmaceutical composition of the present invention can be granulated by adding excipients such as lactose and starch to the binder, if necessary. Granulation may be carried out by any method, but preferred are fluidized bed granulation, spray granulation, agitation granulation, etc. in which a wetting liquid can be atomized and added.

[0011] In addition, when compression molding the granules, a disintegrant or a lubricant can be further used, but when cross-linked sodium carboxymethyl cellulose is used as the disintegrant, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose Compared to cases where other disintegrants such as microcrystalline cellulose are used, tablet quality such as hardness, disintegration time, and surface friability is superior, and it can be used preferably.

[0012] The lactose added as an excipient is powdered lactose,
By using granulated lactose (trade name: Dilactose, manufactured by Freund Sangyo Co., Ltd.), which has a particle shape that has superior fluidity and is more susceptible to plastic deformation than crystalline lactose, it is possible to perform high-speed continuous tableting such as sticking and laminating. Excellent tablet quality can be obtained without any tableting problems that sometimes occur, and it can be used conveniently.

[0013]

EXAMPLES The present invention will be specifically explained by the following examples. Specific surface area 4 obtained by crushing 1,6-dihydro-2-{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid (hereinafter referred to as compound)
m2/g powder, 560 g of hydroxypropyl cellulose SL (manufactured by Nippon Soda Co., Ltd.), and 196 g of powdered lactose.
0g (manufactured by HMS) and 1120g of corn starch (manufactured by Nihon Shokuhin Kogyo Co., Ltd.) were charged into a fluidized granulation coating device Flow Coater FLO-5A type (manufactured by Freund Sangyo Co., Ltd.), and while fluidized in air at an inlet temperature of 65°C. , the solvent (30% ethanol solution) was sprayed at an air pressure of 3 kg/
cm2, and granulated by spraying at an atomizing air amount of 200 NL/min.

After drying, add talc (manufactured by Fuji Talc Co., Ltd.) as a lubricant to 600 g of the sieved granules (manufactured in-house).12.
5g and magnesium stearate (Taihei Chemical) 12.5
g, 33.3 g of cross-linked sodium carboxymethyl cellulose (trade name: Acdisol, manufactured by Asahi Kasei Corporation) as a disintegrant and 341.7 g of granulated lactose (trade name: Dilactose, manufactured by Freund Sangyo Co., Ltd.) were placed in a V-type mixer (manufactured by Shinagawa Seisakusho). and mixed for 12 minutes.

Next, the composition mixed in the V-type mixer was compressed into 240 mg tablets using a tablet machine Collect 12HUK (manufactured by Kikusui Seisakusho) with a punch having a diameter of 8 mm to obtain plain tablets. A film coating layer containing hydroxypropyl methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) as the main component is applied to this bare tablet.
Film tablets containing 12 mg of the compound and 40 mg of the compound per tablet were obtained.

[0016]

[Test example] 1. The film tablets prepared in the above examples, finely divided powders and suspensions of the compounds were used as test drugs, and the pH
An elution test was conducted using 900 ml of the buffer solution (37°C) of No. 5.6 using the paddle method (paddle rotation speed: 100 rpm), and the results are shown in Figure 1. As is clear from FIG. 1, the film tablet of the present invention exhibited a significantly higher dissolution property than a finely divided powder of the compound, and was able to be suspended in a short time without exhibiting water repellency.

2. The same test drugs as in the above test example were orally administered to beagle dogs, and the blood concentrations were measured. Table 1 shows the blood concentration parameters determined from the blood concentrations of each test drug. As is clear from Table 1, the film tablet of the present invention has a higher maximum blood concentration than the finely divided powder of the compound;
The area under blood concentration also showed a large value, indicating that the bioavailability was improved.

Test conditions Test animals: 8 male beagle dogs (10-12 kg) Administration: After fasting for 24 hours, each preparation was mixed with 2 ml of water.
Administered orally by gavage with 0 ml. After administration, the subjects were allowed to drink water freely. Blood collection: before administration, after administration 0.25, 0.5, 0.
75, 1, 1.5, 2, 3, 4, 5 and 8 hours, 2.5 ml was collected from the forearm brachial vein and centrifuged to obtain plasma. Quantification: HPLC using an ultraviolet detector as a detector
Quantitated by method.

[0019]

[Table 1]

[0020]

Effects of the Invention As explained above, according to the present invention, 1,6-dihydro-
2-{2-(2-methylpropoxy)anilino}-6-
The solubility of oxo-5-pyrimidinecarboxylic acid can be increased and the bioavailability can be improved. In addition, it shows excellent productivity in the granulation, tabletting, etc. processes, reduces manufacturing costs, and provides a preparation that is easy to take.

[Brief explanation of the drawing]

FIG. 1 is a diagram showing the results of a dissolution test.

Claims (3)

[Claims] [Claim 1] 1,6-dihydro-2 as an active ingredient
A pharmaceutical composition comprising -{2-(2-methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid, a hydrophilic polymer as a binder, and crosslinked carboxymethyl cellulose sodium as a disintegrant. [Claim 2] 1,6-dihydro-2-{2-(2-
methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid has an average particle diameter of 10 μm or less,
The pharmaceutical composition according to claim 1, having a specific surface area of 2 m2/g to 10 m2/g. [Claim 3] 1,6-dihydro-2-{2-(2-
Pharmaceutical composition according to claim 1, characterized in that it contains 0.2 to 2% by weight of hydrophilic polymer based on the weight of the methylpropoxy)anilino}-6-oxo-5-pyrimidinecarboxylic acid.