JP2538422B2 - Anti-tumor agent in the form of non-injection that suppresses the occurrence of inflammation caused by 5-fluorouracils - Google Patents

Description

Description: TECHNICAL FIELD The present invention contains a 5-fluorouracil (5-FU) compound as an anti-cancer component, and a non-injectable anti-cancer drug and cancer that suppress the occurrence of inflammation caused by 5-fluorouracil compound. Treatment method.

Prior art 5-Fluorouracil (5-FU) has excellent antitumor effect and is widely used clinically as an anticancer agent.
It is known that its administration often causes serious problems such as inflammation in the oral cavity and digestive tract tissues, and diarrhea.

Meanwhile, JGNiedzwic
ki) et al. show that 5-FU is activated by a phosphorylating enzyme in vivo, and this activated substance shows an antitumor effect in cancer cells, but causes inflammation in normal tissues, and certain pyrimidine compounds. Is due to the phosphorylation enzyme
It has been reported to inhibit the activation of FU. [Biochemical Pharmacolog
y), Vol.33, No.15, pp.2383-2395, 1984] Further, JP-B-63-37766 discloses a combination of 5-FUs with a specific triazine compound or pyrimidine compound, The anti-tumor effect of 5-FUs is enhanced,
It is stated that it does not enhance its toxicity and side effects. Although none of the pyrimidine compounds tested in the publication for enhancing the antitumor effect of 5-FUs significantly enhance the side effect of inflammation based on 5-FU,
This cannot be reduced.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide an excellent anticancer agent capable of significantly suppressing the occurrence of inflammation caused by 5-FUs, even though 5-FUs are used as an active ingredient. .

Another object of the present invention is to provide a method for treating cancer while significantly suppressing the occurrence of inflammation caused by 5-FUs.

That is, the present invention contains 5-fluorouracils and oxo acids or pharmaceutically acceptable salts thereof as active ingredients, and the content of oxo acids or pharmaceutically acceptable salts thereof is relative to 5-fluorouracils. A non-injection type carcinostatic agent which suppresses the occurrence of inflammation caused by 5-fluorouracils in an amount of 0.05 to 6 times, and oxonic acid or a pharmacologically acceptable salt thereof, as an active ingredient. The present invention provides a preventive and therapeutic agent for inflammation caused by 5-fluorouracils.

The present inventor has conducted extensive studies on many pyrimidine compounds known as antitumor effect enhancers for 5-FUs, for their antitumor-enhancing effect and anti-inflammatory effect due to administration of 5-FUs. However, most of the compounds that have been confirmed to have an antitumor effect-enhancing effect so far have no or only a low anti-inflammatory effect. However, as a result of continued diligent research, it is expected that oxonic acid exerts a remarkable inhibitory effect on inflammation and diarrhea induced by 5-FUs without substantially reducing the antitumor effect of 5-FUs. I found the fact that not. Moreover, it was confirmed that the effect of such an oxo acid is prominently expressed only in the non-injection form of 5-FU anticancer drug. Thus, according to the present invention, inflammation caused by 5-FUs such as digestive tract inflammation, stomatitis, diarrhea, etc. can be remarkably generated without substantially decreasing the antitumor effect of 5-FUs. Can be suppressed. Moreover, the preparation of the present invention does not increase side effects other than toxicity and inflammation of 5-FUs. Furthermore, it was found that the combination of specific 5-FUs and oxonic acid suppressed the occurrence of inflammation more significantly. The present invention has been completed based on such findings.

As 5-FUs, various substances conventionally known as anticancer agents are included, and although there are differences in their extent, it is known that their administration may induce inflammation. There is. Specifically, various known active ingredients of anticancer agents and, for example, European Patent Publication No. 18
0897, U.S. Patent Application No. 2192880A, JP-A-63-2011
Examples include patent publications such as No. 27, 5-FU derivatives described in the literature, and pharmacologically acceptable salts thereof. As a typical example thereof, for example, 5-fluorouracil (5
-Fu), 5'-deoxy-5-fluorouridine (5 '
DFUR), 1- (2-tetrahydrofuranyl) -5-fluorouracil (FT-207), 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl- Examples thereof include 5-FU derivatives such as 5-fluorouracil (compound a) and pharmaceutically acceptable salts thereof.

Oxonic acid, i.e., 1,4,5,6-tetrahydro-4,6-dioxo-1,3,5-triazine-2-carboxylic acid, has hitherto been mainly used as a reagent for preparing a hyperuricemia model [ Clinical Toxicology, 13 (1), 47 (1978)], and has never been used for the purpose of suppressing inflammation or diarrhea caused by 5-FUs. Oxonic acids naturally include their keto-enol isomers. Salts of oxo acids include both pharmacologically acceptable acid addition salts and basic compound salts. Examples of the acid capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, Examples thereof include malonic acid, methanesulfonic acid, and benzoic acid. Further, examples of the basic compound capable of forming a pharmacologically acceptable basic compound salt include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like. Also,
As the oxo acid, a substance that produces oxo acid in a living body may be used.

The preparation of the present invention is usually prepared by administering the active ingredients 5-FU and oxo acid in one dosage form. It may be administered simultaneously or separately. That is, the oxo acid preparation can be administered at any time before or after the 5-FU preparation is administered.

As described above, the preparation of the present invention is prepared in a mixed preparation form containing 5-FUs and oxo acids, or a preparation form containing 5-FUs and oxo acids alone. In any case, according to the usual method using a suitable carrier for the formulation,
The pharmaceutical composition is in the form of non-injection. Examples of the carrier used here include various substances commonly used for ordinary drugs, for example, fillers, fillers, binders, disintegrants, surfactants, diluents and excipients such as lubricants, and the like. .

The dosage form of the preparation of the present invention is not particularly limited as long as it is a non-injection form, and can be appropriately selected according to the purpose of treatment, and specifically, tablets, pills, powders, solutions, suspensions, emulsions, granules, Capsule, suppository, ointment, mouthwash, oral tablet (troche)
Etc. can be illustrated.

In the case of molding in the form of tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, excipients such as calcium carbonate, carion, crystalline cellulose, silicic acid, simple syrup, glucose solution, starch solution. , Gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, cantera powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl Disintegrating agents such as sodium sulfate, stearic acid monoglyceride, starch, lactose, sucrose,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbents, purified talc, stearates, boric acid powders, lubricants such as polyethylene glycol, etc. can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multi-layer tablets.

In molding into pill form, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic powder, tragacanth powder, gelatin, laminaran, agar And the like can be used.

When molded into a suppository, as a carrier, for example, polyethylene glycol, cocoa butter, higher alcohol,
Esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be used.

Capsules are prepared by mixing oxo acids or 5-FUs with the various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like.

When preparing pastes, creams and gels, for example, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The troche is prepared, for example, by using glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc or the like as a carrier.

A mouthwash is prepared by adding oxonic acid as an active ingredient, if necessary, a suitable carrier and diluting it with a diluent. Further, this is prepared as a preparation of a type for preparation at the time of use, for example, tablets, pills, powders, solutions, suspensions, emulsions, granules and the like containing oxo acid, and dissolved, suspended or suspended in an appropriate diluent at the time of use. It may be emulsified and used. Water can be typically exemplified as the diluent.

Furthermore, colorants, preservatives, flavors, flavors, sweeteners and other pharmaceuticals may be added to the above-mentioned preparations, if necessary.

The amounts of 5-FUs and oxo acids contained in the preparation of the present invention are not particularly limited and may be appropriately selected, but both are usually about 1 to 70% by weight in the preparation.

The administration method of the preparation of the present invention is not particularly limited as long as it is non-injection administration such as enteral administration, oral administration, rectal administration, buccal administration, and transdermal administration, and various formulation forms, patient's age, sex, etc. It is determined according to the condition, the degree of symptoms of the patient, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. Suppositories are administered rectally. The ointment is applied to the skin, the mucous membrane in the oral cavity, and the like.

The dose of the preparation of the present invention can be appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease and the like. Usually 5
-The amount of FUs is about 1 to 100 mg / kg / day, preferably 4 to 20 m
About g / kg / day, the amount of oxonic acid is in the range of 1 to 100 mg / kg / day, preferably 2 to 30 mg / kg / day. The ratio of 5-FUs and oxo acid or a salt thereof used in the above-mentioned formulation is 0.05
The weight may be in the range of 6 to 6 times. The formulation of the present invention can be administered in 1 to 4 divided doses per day. In the case of the preparation of the present invention in the form of a mouthwash, the application amount is a liquid form of about 0.1 to 10 mg oxonic acid / ml (final concentration), similar to a general mouthwash, and 100 to 300 ml per day. Appropriate amounts are used, which can be used multiple times a day.

EXAMPLES Hereinafter, the present invention will be further clarified by listing pharmacological test examples and formulation examples.

Pharmacological Test Example 1 <Gastrointestinal Inflammation Inhibitory Action Test> (a) Preparation of Test Liquid I 3-3 [−) 6-benzoyloxy-3-cyano-2
-Pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil (hereinafter referred to as compound a) was suspended in a 1% hydroxypropylmethylcellulose solution at a concentration of 4.0 mg / ml, and the suspension was allowed to stand at room temperature. After stirring with a stirrer for about 20 minutes, ultrasonic treatment was performed for 5 minutes under ice cooling to obtain a test solution (1).

To this is added potassium oxonate at concentrations of 0.2, 0.5 and 1.
Test liquids (2) to (6) were obtained in the same manner as above, adding 0, 2.0 and 5.0 mg / ml.

(B) Preparation of test liquid II In place of compound a in the above I, 5'DFUR was added at a concentration of
The concentration of 5-FU is 4.0 mg / ml so that it becomes 20.0 mg / ml.
In addition, UFT [Daiho Pharmaceutical Co., Ltd. Uras and F
5% gum arabic suspension containing T-207 and 4: 1] FT-2
Each of 07 was suspended in 1% hydroxypropylmethylcellulose solution so as to have a concentration of 4.0 mg / ml, stirred at room temperature for about 20 minutes with a stirrer, and then sonicated for 5 minutes under ice cooling to perform the test. Liquids (7), (13) and (18) were obtained.

The concentration of potassium oxonate in the test liquid (7) was 0.
Test liquids (8) to (12) were obtained in the same manner by adding 2, 0.5 and 1.0, 2.0 and 5.0 mg / ml.

The concentration of potassium oxonate in the test solution (13) was 0.5
And 1.0, 2.0 and 5.0 mg / ml, and in the same manner, test liquids (14) to (17) were obtained.

Further, the concentration of potassium oxonate in the test liquid (18) is
Test liquids (19) to (22) were obtained in the same manner by adding 0.5 and 1.0, 2.0 and 5.0 mg / ml.

(C) Anti-cancer experiment 2 × 10 subcutaneously on the back of 5-week-old male Don-Ryu rats
^Four Yoshida sarcoma cells were transplanted. From 24 hours after the transplantation, 1.0 ml of each of the above-mentioned test liquids (1) to (22) was orally administered to the rat body weight of 100 g once a day. The administration was performed for 7 days. The tumor-bearing rats in the control group
Only a 1% hydroxypropylmethylcellulose solution was orally administered.

On the 8th day after the tumor implantation, the rat was sacrificed, and the tumor and the digestive tract tissue were taken out. The weight of the excised tumor was measured, and the tumor reduction rate (%) was calculated by the following formula.

Tumor reduction rate = [1- (T / C)] × 100 T: Tumor weight of test liquid administration group (g) C: Tumor weight of control group (g) A section sample was prepared from the excised gastrointestinal tract. Was observed with an optical microscope to examine the incidence of inflammation in the digestive tract. Inflammation frequency is based on the number, (-) no inflammation,
(+) Mild inflammation, (++) Moderate inflammation, (+++)
It was divided into four grades of severe inflammation. The section specimens were obtained by opening the excised digestive tract, washing with physiological saline, and immersing and fixing in a 10% neutral buffered formalin solution. The incidence (%) of inflammation above mild inflammation was defined as the frequency of gastrointestinal inflammation. The results are shown in Table 1 below.

Comparative Pharmacological Test Example (a) A combination of allopurinol, which is known to have a phosphorylation-inhibiting action of 5-FU, and compound a (4 mg / 100 g) was performed in the same manner as above, and the tumor shrinkage rate (%) was measured in rats. )
The relationship between the incidence of gastrointestinal inflammation (%) was investigated. The result
The results are shown in Table 2 below.

(B) In combination with the compound described in JP-B-63-37766, which suppresses weight loss due to 5-FUs, and compound a (4 mg / 100 g), and in the same manner as above, the tumor shrinkage rate per 7 rats ( %) And the frequency of gastrointestinal inflammation (%). The results are shown in Table 3 below.

(B) From the results of Tables 1 to 3, 5 of various concomitant drugs
-A dose that reduces the tumor reduction rate of FUs alone by 10% (A, mg / 100g), and a dose that reduces the incidence of gastrointestinal inflammation to half that of 5-FUs alone (B, mg / 100g). The effect coefficient (A / B) was calculated. The results are shown in Table 4 below.

As shown in Table 4, potassium oxonate has a significantly higher effect coefficient for 5-FUs than other concomitant agents.
It was suggested that it would be extremely useful as a concomitant drug of the same class.

Pharmacological Test Example 2 <Test for Preventing Diarrhea> This test was carried out by using beagle dogs to test the effect of preventing oxonic acid on the occurrence of diarrhea caused by a large amount and continuous administration of 5-FUs, and is carried out as follows. It was

That is, four beagle dogs with a body weight of 10 to 12 kg were used in the experimental group (A).
2 animals and 2 animals in experimental group (B) were divided into 75 mg / kg / day of compound a in the control group (1 animal) and 75 mg of compound a in the test group (1 animal) in the experimental group (A). Oxonic acid 20m / kg / day
It was administered in combination with g / kg / day.

Further, in the experimental group (B), the compound a was added to the control group (1 animal).
50 mg / kg / day of the compound a in the test group (1 animal)
Oxonic acid 10 mg / kg was used in combination with 0 mg / kg / day.

Powders of the above-mentioned respective test substances were packed in gelatin capsules and administered by oral gavage.

From the start of oral administration, twice daily in the morning and evening, the stool condition of the gurgle dog was observed, and the occurrence of loose stools and watery stools was regarded as the day of diarrhea, and the number of days until the onset was calculated.

 The results obtained are shown in Table 5 below.

From Table 5 above, diarrhea occurred in the compound a single administration group (control group) 5 to 7 days after the start of administration, but diarrhea was delayed in the oxo acid combination group (test group) by 14 to 15 days. Was done. In addition, the combined use of oxonic acid was able to increase the dose of compound a before the occurrence of diarrhea.

Pharmacological test example 3 <Intraoral inflammation therapeutic effect test> This test was conducted by using beagle dogs to examine the recovery effect of oxo acid application on oral inflammation (stomatitis) caused by continuous administration of a large amount of 5-FUs. Yes, it was done as follows.

That is, two beagle dogs identical to those used in Pharmacological Test Example 2 were used as a control group (1 dog) and a test group (1 dog), and 50 mg / kg of compound a was placed in a gelatin capsule and administered by oral gavage. did. The administration was continuously performed for 6 days per week.

After the occurrence of stomatitis, the control group was continuously administered with 50 mg / kg of compound a in the same manner as above.

In the test group, after the occurrence of stomatitis (the 11th day from the start of administration of an anticancer agent), the ointment containing oxonic acid was further applied twice a day in the morning and evening (1 g per time) to the inflamed site of the oral cavity while continuing the administration of the compound a. As the above ointment, potassium oxonate was added to olive oil-containing exposed beeswax ointment at 20 mg / g,
The one kneaded uniformly was used.

The oral cavity of the beagle dog was visually observed at the time of administration of the compound a, and the degree of inflammation was evaluated according to the following four grades according to the section of stomatitis as a side effect of the Japan Cancer Treatment Society.

-... nothing, + ... pain, erythema, blistering ++ ... erosion, ulcer, ++++ ulcer, bleeding, non-eating results

From the above Table 6, it was suggested that by applying oxonic acid into the oral cavity after the occurrence of stomatitis, the progress of inflammation can be prevented and further recovered.

Formulation Example 1 Potassium oxonate 60 mg Starch 112 mg Magnesium stearate 18 mg Lactose 45 mg Total 235 mg A tablet having the above composition was produced in a tablet by a conventional method.

Formulation Example 2 Compound a 50 mg Potassium oxonate 25 mg Starch 112 mg Magnesium stearate 18 mg Lactose 45 mg Total 250 mg Tablets of the above composition were prepared in a tablet by a conventional method.

Formulation Example 3 5'-DFUR 250 mg Potassium oxonate 13 mg Starch 112 mg Magnesium stearate 20 mg Lactose 45 mg Total 440 mg A tablet having the above composition was prepared in a tablet by a conventional method.

Formulation Example 4 5-FU 50 mg Potassium oxonate 20 mg Starch 112 mg Magnesium stearate 18 mg Lactose 45 mg Total 245 mg A tablet having the above composition was produced by a conventional method in one tablet.

Formulation Example 5 FT-207 200 mg Potassium oxonate 50 mg Starch 237 mg Magnesium stearate 18 mg Lactose 45 mg Total 550 mg A tablet having the above composition was produced by a conventional method in one tablet.

Formulation Example 6 Potassium oxonate 2 g Glycerin 10 g Head oil 0.2 g Ethanol 10 g Water 77.8 g Total 100 g A mouthwash having the above composition was prepared in 100 ml by a conventional method.

Claims (3)

(57) [Claims] 1. Containing 5-fluorouracils and oxo acid or a pharmaceutically acceptable salt thereof as an active ingredient,
Oxonic acid or its pharmaceutically acceptable salt content is 5
-0.05 to 6 times the weight of fluorouracils,
A non-injection type anticancer agent that suppresses the occurrence of inflammation caused by 5-fluorouracils. 2. 5-fluorouracils are 5-fluorouracil, 5'-deoxy-5-fluorouridine, 1
-(2-Tetrahydrofuranyl) -5-fluorouracil, 3- [3- (6-benzoyloxy-3-cyano-
The anticancer agent according to claim 1, which is at least one selected from the group consisting of 2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil, derivatives thereof and pharmaceutically acceptable salts thereof. 3. A preventive and therapeutic agent for inflammation caused by 5-fluorouracils, which comprises oxo acid or a pharmacologically acceptable salt thereof as an active ingredient.