JPH05310571A - Anti-cancer medicine composition of amorphous benzoylurea-based compound - Google Patents

Abstract

PURPOSE:To obtain an anti-cancer medicine composition of amorphous benzoylurea compound having excellent water solubility and absorption from digestive tubes, comprising a benzoylurea compound and a water-soluble polymer compound. CONSTITUTION:A benzoylurea compound of the formula (X is halogen or nitro; Y is Y, halogen, nitro, methyl, ethyl or trifluoromethyl; Z1 is halogen or trifluoromethyl; Z2 is H or halogen; A is CH or N) and a water-soluble polymer compound (e.g. hydroxypropylmethyl cellulose phthalate) are dissolved in a solvent (e.g. acetone) to give a solution, from which the solvent is removed to give a medicine composition. 0.5-15 pts.wt. water-soluble polymer compound and 30-200 pts.wt. solvent are used based on 1 pt.wt. compound of the formula. The medicine composition can suppress harmful reaction and disorder caused by administration in a large amount.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an amorphous benzoylurea compound which is composed of a specific benzoylurea compound having anticancer activity and a water-soluble polymer compound and which has enhanced absorption from the digestive tract. The present invention relates to an anticancer pharmaceutical composition and a method for producing the same.

[0002]

2. Description of the Related Art The following general formula (Formula 2):

[Chemical 2] (In the formula, X is a halogen or nitro group, Y is hydrogen, a halogen, a nitro group, a methyl group, an ethyl group or a trifluoromethyl group, Z ₁ is a halogen or a trifluoromethyl group, and Z ₂ is hydrogen or a halogen. , A represents CH or nitrogen), and the benzoylurea compounds are substantially known compounds, and are known to have excellent anticancer activity (JP-A-57-109721). , 61-
1670, 61-93163 and 63-990.
No. 56).

The above-mentioned benzoylurea compounds are poorly soluble in water and therefore have poor absorbability from, for example, the digestive tract. Therefore, in order to exert a sufficient anti-cancer activity, it is necessary to increase the dose, but adverse reactions and disorders due to large dose administration are feared.

Therefore, various pharmaceutical compositions having excellent absorbability of the benzoylurea compounds from the digestive tract have been proposed (Japanese Patent Laid-Open Nos. 61-27965 and 61-1916).
No. 23, No. 62-185013, No. 64-79154.
JP-A-1-93527, JP-A-2-796999 and JP-A-2-196719).

[0005]

However, even with the above-mentioned pharmaceutical composition, the absorption of benzoylurea compounds from the gastrointestinal tract is still not sufficient, and the emergence of a new pharmaceutical composition capable of enhancing this absorption is not possible. Is desired. An object of the present invention is to provide an anti-cancer pharmaceutical composition of an amorphous benzoylurea compound, which has a significantly improved solubility in water and a significantly improved absorbability from the digestive tract.

[0006]

Means for Solving the Problems The present invention will be summarized. The first invention of the present invention relates to an anticancer pharmaceutical composition, which is represented by the following general formula (Formula 3):

[Chemical 3] (In the formula, X is a halogen or nitro group, Y is hydrogen, a halogen, a nitro group, a methyl group, an ethyl group or a trifluoromethyl group, Z ₁ is a halogen or a trifluoromethyl group, and Z ₂ is hydrogen or a halogen. And A represents CH or nitrogen), which is an anticancer pharmaceutical composition of an amorphous benzoylurea compound composed of a benzoylurea compound and a water-soluble polymer compound. Also,
A second invention of the present invention is an invention relating to the method for producing the anticancer pharmaceutical composition of the first invention, which is a benzoylurea compound represented by the general formula (Formula 3) and a water-soluble polymer. The compound is dissolved in a solvent and the solvent is removed to form an anticancer pharmaceutical composition of an amorphous benzoylurea compound composed of the benzoylurea compound and a water-soluble polymer compound. To do.

The inventors of the present invention have conducted various investigations with the aim of increasing the absorbability of the benzoylurea compound from the digestive tract, and as a result, the amorphous compound comprising the benzoylurea compound and the water-soluble polymer compound has been obtained. The present invention has been completed by finding that a pharmaceutical composition of a qualitative benzoylurea compound can enhance the absorbability of the benzoylurea compound from the digestive tract.

In the general formula (Formula 3), examples of halogen include chlorine, bromine, iodine and the like.

As the benzoylurea-based compound,
For example, a compound represented by the following formula is exemplified.

[0010]

[Chemical 4]

However, any benzoylurea compound having an anticancer action can be used without particular limitation to the benzoylurea compound represented by the above general formula (Formula 3). You can expect an effect. The benzoylurea compounds are generally known compounds, and are produced, for example, by the method described in JP-A-57-109721 or a method analogous thereto.

As described above, the anticancer pharmaceutical composition of the amorphous benzoylurea compound of the present invention removes the solvent from the solution prepared by dissolving the benzoylurea compound and the water-soluble polymer compound in the solvent. It can be manufactured by

The water-soluble polymer compound used in the present invention includes polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, solid polyethylene glycol, hydroxypropylmethylcellulose phthalate,
Hydroxypropyl methyl cellulose acetate succinate, ethyl methacrylate acrylate copolymer, methyl methacrylate methyl methacrylate copolymer, ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate chloride copolymer, and the like. One or more components selected from the group can be used. Among them, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate, acetate succinate of hydroxypropyl methyl cellulose, ethyl acrylate methacrylate copolymer, methyl methacrylate methacrylate copolymer and the like are preferable because they have enteric properties, hydroxy, Propylmethyl cellulose phthalate is even more desirable. The mixing ratio of the water-soluble polymer compound to the benzoylurea-based compound varies depending on the components used and cannot be said to be unequivocal, but, relative to 1 part by weight of the benzoylurea-based compound,
Usually, it is 0.5 to 15 parts by weight, preferably 1 to 5 parts by weight.

Any solvent may be used as long as it can dissolve the benzoylurea compound and / or the water-soluble polymer compound, but both the benzoylurea compound and the water-soluble polymer compound are dissolved. Those that do are desirable. Examples of the solvent here include alcohols such as methanol and ethanol, ketones such as acetone, ethers such as tetrahydrofuran,
Examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, esters such as ethyl acetate, among which ethanol, acetone, tetrahydrofuran, methylene chloride and the like are preferable. The amount of the solvent used is 500 parts by weight or less, preferably 30 to 200 parts by weight, based on 1 part by weight of the benzoylurea compound, and 100 parts by weight or less, based on 1 part by weight of the water-soluble polymer compound.
It is preferably 3 to 10 parts by weight.

Next, regarding the compounding order of each component, it is preferable that the benzoylurea compound is first dissolved in a solvent and then the water-soluble polymer compound is dissolved therein, but each component is dissolved in each solvent. It is also possible to mix the dissolved solutions simultaneously. When the dissolution rate of each of these components is slow, the solvent may be heated to a temperature equal to or lower than the boiling point to be dissolved in advance.

Further, as a method for removing the solvent from the solution in which the benzoylurea compound and the water-soluble polymer compound are dissolved, a method which is usually carried out industrially, for example, heating under normal pressure or reduced pressure is performed. Method, thin film drying method, spray drying method, freeze drying method and the like.

As a method of removing the residual solvent in the pharmaceutical preparation, a method of subjecting the composition obtained by removing the solvent by an ordinary method to the following post-treatment, for example,
If necessary, the composition is pulverized with a hammer mill, a pin mill, etc., and further finely pulverized with a jet mizer, etc.,
There is a method of removing the residual solvent by drying under normal pressure or reduced pressure.

The composition obtained by such a method or the composition from which the residual solvent has been removed is used to prepare tablets, capsules, enteric agents, granules, powders, fine granules and the like by a conventional method. can do.

[0019]

EXAMPLES Examples will be described below to explain the present invention in more detail, but they do not limit the present invention.

Example 1 To 15 g of a benzoylurea compound (the above compound 3) was added 1.5 liter of acetone, and the mixture was heated to about 50 ° C. and dissolved. On the other hand, to 30 g of polyvinylpyrrolidone K-30 (manufactured by Nacalai Tesque, Inc.), 200 ml of ethanol is added and dissolved. After mixing these two solutions, about 80
These solvents were distilled off under reduced pressure using an evaporator on a water bath at ℃ to obtain 45 g of Composition A.

40 g of the composition A obtained here was crushed at 20,000 rpm using a centrifugal crusher [manufactured by Nippon Seiki Seisakusho Co., Ltd., using 0.12 m / m screen], and further, TJ60 type counter jet mill [turbo. Industry Co., Ltd.
Manufacture], and then under reduced pressure (0.35 mmHg) 80
Composition B37 after drying at 40 ° C for 4 days to remove residual solvent
g (10 ppm or less of residual solvent at this time) was obtained.

Next, the benzoylurea compound (Compound 3), Compound 3 and polyvinylpyrrolidone K-30 of the above composition B were subjected to powder X-ray diffraction.
Was compared with a physical mixture (hereinafter, abbreviated as a comparative product). As a result, the powder X-ray diffraction pattern of the above composition B showed a halo pattern, which was different from that of the comparative product, indicating that the compound 3 of the above composition B was amorphous. It was

Example 2 In the same manner as in Example 1 except that the dissolution at about 50 ° C. using 1.5 liter of acetone in Example 1 was replaced with the dissolution at room temperature using 600 ml of tetrahydrofuran, 37 g of composition C from which the residual solvent was removed (80 ppm of residual solvent at this time) was obtained.

When the crystallinity of the compound 3 of the composition C was examined in the same manner as in Example 1, it was found to be amorphous.

Example 3 To 15 g of the benzoylurea compound (the above compound 3) and 30 g of polyvinylpyrrolidone K-30, 3 liters of methylene chloride was added, and the mixture was heated to about 35 ° C. and dissolved to obtain a solution. With respect to this solution, these solvents were distilled off under reduced pressure using an evaporator on a water bath at about 80 ° C. to obtain a composition D, which was pulverized in the same manner as in Example 1 above, and then reduced in pressure. It was dried at 80 ° C. for 1 day under (0.35 mmHg) to obtain 37 g of a composition E from which the residual solvent was removed (the residual solvent at this time was 10 ppm or less).

When the crystallinity of the compound 3 of the composition E was examined in the same manner as in Example 1, it was found to be amorphous.

Example 4 750 ml of acetone was added to 7.5 g of the benzoylurea-based compound (the above compound 3), and the mixture was heated to about 50 ° C. and dissolved. On the other hand, polyvinylpyrrolidone VA-64 (trade name;
250 ml of ethanol was added to 37.5 g of Kollidon VA-64 (manufactured by BISF) to dissolve. After mixing these two solutions, these solvents were distilled off under reduced pressure using an evaporator on a water bath at about 80 ° C. to obtain a composition F14.0 g. The composition obtained here was added to a centrifugal pulverizer [manufactured by Nippon Seiki Seisakusho Ltd., 0.1
m / m screen is used], the powder is pulverized at 10,000 rpm, sized by a sieve (250 μm to 74 μm), and then at 80 ° C. under reduced pressure (0.9 mmHg or less).
3.9 g of composition G dried for days to remove residual solvent
(The residual solvent at this time was 100 ppm or less).

When the crystallinity of the compound 3 of the composition G was examined in the same manner as in Example 1, it was found to be amorphous.

Example 5 700 g of acetone was added to 7.5 g of a benzoylurea compound (the above compound 3) and 37.5 g of hydroxypropylmethyl cellulose phthalate (trade name; HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.), and the mixture was added at about 50 ° C. After heating to dissolve the solvent, these solvents were distilled off under reduced pressure using an evaporator on a water bath at about 80 ° C. to obtain 44.2 g of Composition H. 44.2 g of the composition H obtained here was pulverized at 10,000 rpm using a centrifugal pulverizer (manufactured by Nippon Seiki Seisakusho Co., Ltd., using 0.1 m / m screen),
After sieving with a sieve (μm to 74 μm), it was dried under reduced pressure (0.9 mmHg or less) at 80 ° C. for 20 days to remove residual solvent 15.56 g of composition I (residual solvent at this time 100 ppm or less) ) Got.

When the crystallinity of the compound 3 of the composition I was examined in the same manner as in Example 1, it was found to be amorphous.

Example 6 14.3 g of benzoylurea compound (the above compound 3)
And hydroxymethyl cellulose phthalate (HP-5
5), add 1 liter of acetone to 71.4 g and add about 50
After dissolving by heating to ℃, insoluble matter is removed by natural filtration, and closed system spray dryer CL-8 type [Okawara Kakohki Co., Ltd.] is used using a rotary tube pump.
The composition J 85 was operated for 18 minutes at a throughput of 1.7 kg / hr, a spray dryer disk nozzle rotation speed of 20,000 rpm, and an inlet temperature of 100 ° C.
g was obtained. This was dried for 3 days to remove the residual solvent to obtain 72 g of Composition K (100 ppm or less of residual solvent at this time).

When the crystallinity of the compound 3 of the composition K was examined in the same manner as in Example 1, it was found to be amorphous.

Comparative Example 1 Decaglycerin monolaurate [trade name: Decagrin 1
-L, manufactured by Nikko Chemicals Co., Ltd.] 3.90 g of water 5
0.74 g was added and dissolved, and 23.42 g of the benzoylurea-based compound (Compound 3) was added and suspended therein, and this was placed in a 0.16 liter container, and glass beads (0.25-0.25) were added thereto. 0.5mmφ) is filled up to the full container, and Dyno Mill (trade name: KDL type, wheelie.
Wet grinding (3,0 manufactured by A. Berkofen)
00 rpm × 45 minutes). After the pulverization was completed, the glass beads were removed with a sieve to obtain 67 g of a suspending agent.

29.1 g of sucrose monopalmitic acid ester (trade name: P1670, manufactured by Mitsubishi Kasei Foods Co., Ltd.) was added to 50 g of the above-mentioned suspending agent, frozen with dry ice / methanol, and vacuum dried for 24 hours. Water was removed to obtain a composition L. The powder X-ray diffraction pattern of composition L showed that compound 3 was crystalline. Furthermore, 3.9 g of light anhydrous silicic acid was added to Composition L and mixed to obtain 50.5 g of comparative powder M (this comparative powder is disclosed in JP-A-2-196).
719).

Test Example 1 (Dissolution Test) The test was carried out by the paddle method of Japanese Pharmacopoeia 11 “Dissolution Test Method”. First, 500 ml of water was placed in a container, and further, the composition B of Example 1 or the comparative powder M of Comparative Example 1 was placed in an amount corresponding to 4 mg in terms of a benzoylurea compound (Compound 3), It was stirred at 50 rpm. The elution amount was measured by collecting 10 ml of water in the container over time, and collecting the collected water for 10 minutes with a centrifuge (50,000).
rpm) and the supernatant is detected with HPL at a detection wavelength of 254 nm.
Performed using C. The results (amount of Compound 3 eluted with respect to water) are shown in Table 1 below.

[0036]

[Table 1]

As is clear from the above results, it is understood that the pharmaceutical composition of the amorphous benzoylurea compound of the present invention has better dissolution properties than conventional powders.

Test Example 2 (Test for confirming absorption site of benzoylurea compound) A drug absorption test from a rat digestive tract loop was conducted under the following test conditions. Animal: Rat SD SPF (male, weight 250-300)
g), n = 2 Dose: Composition G is converted to a benzoylurea compound (Compound 3) and administered at 75 mg / Kg. Administration site: stomach; upper small intestine from gastric pylorus to cardia; upper gastric exit to small intestine Up to 10 cm in the lower small intestine; below the gastric cardia, 10 cm from the small intestine to the cecal entrance Large intestine; from the cecum entrance to the anus Administration: Rats are anesthetized with Nembutal injection solution, followed by laparotomy, and sutures at each administration site It was ligated with and the drug was administered with an injection needle. The drug was suspended in purified water and administered within 1 hour after suspension. Feeding condition: fasting for 20 hours before administration, free water intake Blood collection time: 1, 2, 3, 4 hours after administration Measurement of plasma concentration: pretreatment of collected plasma, HPLC
(C18-based reverse phase column, mobile phase: mixed solution of acetonitrile-water 1: 1, detection: UV265 nm). The result is shown in FIG.

As is clear from the above results, it is understood that the amorphous benzoylurea compound is absorbed from the intestinal tract.

Test Example 3 (test for confirming enteric properties) A dissolution characteristic test was carried out at different pH (1.2 or 6.5) by the paddle method of Japanese Pharmacopoeia 11 "Dissolution Test".
After the start of the test, the test solution was sampled over time, and the replenisher was supplemented in the same amount as the sampled amount for each sample, and the elution concentration was corrected by the amount.
The test conditions are shown below. Test method: Japanese Pharmacopoeia 11 paddle method Test solution: Japanese Pharmacopoeia 11 "Disintegration test" first solution (pH
After the test in 1.2) for 1 hour, 10 ml of a replacement liquid for pH conversion was added in place of the replenisher to adjust the pH of the test liquid to 6.5, and the test was conducted continuously. (Replacement solution for pH conversion) Potassium dihydrogen phosphate 170.1 g Sodium hydroxide 83.6 g ─────────────────────── Purified water 500 ml Rotation speed: 50 rpm Test liquid temperature: 87 ° C. Amount collected: 5 ml Replenisher liquid amount: 5 ml Amount of drug added: 4 mg equivalent of the composition I converted to a benzoylurea compound (compound 3) Sampling time: 15, 30, 45 after the start of the test , 60, 75,
90, 105, 120, 180, 240 minutes Elution concentration measurement: The collected solution was centrifuged (5000 rpm) for 10 minutes, and the supernatant was analyzed by HPLC at a detection wavelength of 254 nm. The result is shown in FIG.

As is clear from the above results, the composition I of the present invention does not dissolve at pH 1.2 (acidity inside the stomach) but dissolves at pH 6.5 (acidity inside the intestine). ..

Test Example 4 (Absorbability Test I) Using the composition B of Example 1 or the comparative powder M of Comparative Example 1 under the following conditions, an absorbency test in dogs (concentration of Compound 3 in plasma) I went. Animals: Beagle dogs (male, weight approximately 10 kg), 5 in each group. Dose: 25 mg / kg body weight of benzoylurea compound (Compound 3). Administration method: Each of the composition B or the comparative powder M was filled in a gelatin capsule No. 000 and orally administered. Feeding condition: free feeding, free drinking Blood sampling time: before administration, after administration 1, 2, 4, 8, 12, 2
4, 48, 72, 144, 240 hours

The concentration of compound 3 in plasma was determined by pretreating the collected plasma by HPLC (C ₁₈ reverse phase column, mobile phase: acetonitrile-water 1: 1 mixture, detection: UV.
265 nm). The results are shown in Table 2.

[0044]

[Table 2]

As is apparent from the above results, the pharmaceutical composition of the amorphous benzoylurea compound of the present invention has better absorbability than conventional powders.

Test Example 5 (Absorption Test II) A drug absorption test using beagle dogs was carried out under the following test conditions. Animals: Beagle dog (male, body weight about 10 kg), 3 in each group. Dosage: 9.5 mg / kg as benzoylurea compound (Compound 3) Administration method: Each of Compositions G or I was filled in gelatin capsule No. 4 and orally administered. Feeding conditions: postprandial administration (solid feed approximately 300 g), free water intake Blood collection time: before administration, after administration 1, 2, 4, 8, 12, 2
4, 48, 72, 144 hours Measurement of plasma concentration: Pre-treatment of blood-collected plasma and HPLC
(C18-based reverse phase column, mobile phase: mixed solution of acetonitrile-water 1: 1, detection: UV265 nm). The results are shown in Table 3 below.

[0047]

[Table 3]

As is clear from the above results, HP-5
Composition I using Polyvinylpyrrolidone VA-64
It can be seen that the absorbency is superior to that of the composition G using.

Test Example 6 (Absorption Test III) A drug absorption test in rats was conducted under the following test conditions. Animal: Rat SD SPF (male, weight 240-270)
g), n = 5 Dose: 5 mg / Kg of each composition I and K converted to benzoylurea compound (Compound 3) Administration method: 0.5% CM of each composition I or K
The suspension was made with a C-Na aqueous solution (pH 4.0) and orally administered immediately after suspension. Feeding conditions; free feeding, free drinking Blood collection time: 1, 2, 4, 8, 12, 24, 48 after administration
72 Each time Measurement of plasma concentration: Pretreated blood samples were collected and then HPLC
(C18-based reverse phase column, mobile phase: mixed solution of acetonitrile-water 1: 1, detection: UV265 nm). The results are shown in Table 4 below.

[0050]

[Table 4]

As is clear from the above results, HP-5
It can be seen that, in the composition using No. 5, almost the same results are obtained even if the production methods (evaporator method and spray dry method) are different.

[0052]

According to the pharmaceutical composition of the present invention, the benzoylurea compound has a significantly improved solubility in water,
Also, in animal experiments, oral administration can significantly improve the absorbability from the digestive tract, so adverse reactions due to large doses,
The obstacle can be suppressed.

[Brief description of drawings]

BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Compound 3 from rat gastrointestinal loop.
It is a figure showing absorption of.

FIG. 2 is a diagram showing dissolution characteristics of Compound 3 when Composition I is applied to a test solution having a constant pH.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Toru Iwao 2-25-1 Otani, Hirakata, Osaka Prefecture

Claims (2)

[Claims] 1. The following general formula (Formula 1): (In the formula, X is a halogen or nitro group, Y is hydrogen, a halogen, a nitro group, a methyl group, an ethyl group or a trifluoromethyl group, Z ₁ is a halogen or a trifluoromethyl group, and Z ₂ is hydrogen or a halogen. , A is CH or nitrogen), and an anticancer pharmaceutical composition of an amorphous benzoylurea compound comprising a benzoylurea compound and a water-soluble polymer compound. 2. The method for producing the anticancer pharmaceutical composition according to claim 1, wherein the benzoylurea compound represented by the general formula (Formula 1) and a water-soluble polymer compound are dissolved in a solvent. A solvent is removed from the benzoylurea compound to form an anticancer pharmaceutical composition of the amorphous benzoylurea compound comprising the benzoylurea compound and a water-soluble polymer compound. A method for producing an anticancer pharmaceutical composition of a compound.