JPH06340531A - Carcinostatic agent composition for peroral administration - Google Patents

Abstract

PURPOSE:To obtain a pharmaceutical composition having improved peroral absorptivity and containing a 2'-deoxy-2'-methylidenecytidine compound useful as a carcinostatic agent by its remarkable degenerative action on solid tumor, etc. CONSTITUTION:This carcinostatic agent composition for peroral administration contains a 2'-deoxy-2'-methylidenecytidine compound of the formula (R is H or halogen; R<1> and R<2> are H, halogen or 1-4C alkyl), its acid addition salt or its hydrate and a sucrose fatty acid ester, especially a sucrose fatty acid ester having an HLB value of about 10-20. Examples of the compound of formula, its acid addition salt or its hydrate are 2'-deoxy-2'-methylidenecytidine dihydrate, 2'-deoxy-2'-methylidenecytidine hydrochloride 1/2 hydrate, 2'-deoxy-2'- methylidene-5-fluorocytidine,2'-deoxy-2'-fluoromethylidenecytidine and 2'-deoxy-2'- ethylidenecytidine. The absorbability of the compound of formula through digestive tracts, especially the peroral absorbability at a high administration rate, is remarkably improved in this composition.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a 2'-deoxy-2'-methylidene cytidine compound, an acid addition salt thereof or a hydration thereof, which is useful as a carcinostatic agent such as having a remarkable degeneration effect on solid tumors. The present invention relates to a pharmaceutical composition containing a substance and having improved oral absorption, and is used in the medical field.

[0002]

2. Description of the Related Art 2'-deoxy-2'-methylidenecytidine (hereinafter referred to as DMD)
It is known that its acid addition salt or its hydrate is useful as a carcinostatic agent (JP-A-63-258818, JP-A-2-13829).
No. 2, JP-A-3-240794).

[0003]

It has been confirmed that DMDC dihydrate exhibits an excellent antitumor effect, and is currently clinically used as an injection (JP-A-3-240731). However, administration by injection is not only painful for the patient, but also has many problems such as the problem of local injury at the injection site and the need for outpatient treatment. In order to solve these problems, development of an oral preparation is desired. The present inventors conducted basic experiments to develop an oral preparation of DMDC dihydrate, and as the dose was increased, the oral absorption rate was remarkably reduced, and as a result, the bioavailability of DMDC dihydrate was decreased. It turned out to be low. That is, DMDC2
To measure the oral absorption rate of hydrate, radiolabeled DMDC dihydrate was orally administered to rats, and the urinary excretion rate within 24 hours (% of the dose) was examined. / Kg dose was 74.4 ± 1.4%, whereas high dose of 30 mg / kg was 47.2 ± 1.4%.
It fell to 9.6%. Therefore, in order to exert a sufficient pharmacological effect by oral administration, a method of improving the oral absorbability of DMDC dihydrate by performing an appropriate pharmaceutical treatment is desired. By the way, as an absorption promoter used for improving oral absorbability, a carbon number of 8 to 14 is used.
Individual fatty acids (eg sodium caprate) have been reported. Therefore, a composition prepared by mixing DMDC dihydrate with sodium caprate was examined, but no improvement in oral absorption was observed. Surfactants are used in liquid formulations or semi-solid formulations for the purpose of improving the wetting of drugs by water. However, it is generally not practiced to add a surfactant to DMDC dihydrate which is a solid preparation and is easily wet with water as in the present invention. In addition, even with nonionic surfactants, the effect of improving oral absorption was not observed even when blending polyoxyethylene hydrogenated castor oil, polyoxyethylene (20) sorbitan monooleate and the like. On the other hand, when sodium oleate or sodium lauryl sulfate was added, the absorption rate in situ was improved, but the in vivo urinary excretion rate was poor and there was a problem. In addition, a formulation containing these has problems in terms of stability and mucosal damage. The present invention is a DMDC
An object of the present invention is to provide a carcinostatic agent composition containing a 2'-deoxy-2'-methylidene cytidine compound represented by dihydrate and having improved oral absorption.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that sucrose fatty acid esters, particularly HLB value [Hydrophilic-lipophilic balanc
e: Journal of the Society of Cosmetic Chemists, 13
11-1326 (1949)] It was found that about 10 to 20 sucrose fatty acid esters exert a remarkably excellent effect in improving the oral absorbability of DMDC dihydrate at a high dose, and have completed the present invention. .

That is, the present invention is as follows. (1) General formula

[Chemical 2] (In the formula, R represents hydrogen or halogen, and R ¹ and R ² are the same or different and each represents hydrogen, halogen or carbon number 1 to 4;
Is alkyl. 2'-deoxy- represented by
A carcinostatic composition for oral administration comprising a 2'-methylidene cytidine compound, an acid addition salt thereof or a hydrate thereof and sucrose fatty acid ester. (2) The anticancer composition for oral administration according to (1) above, which contains a sucrose fatty acid ester having an HLB value of about 10 to 20. (3) Oral administration according to the above (1), wherein the content of the sucrose fatty acid ester is 0.1 to 20 times the weight of the compound of the general formula (I), its acid addition salt or its hydrate. Anti-cancer drug composition. (4) The 2'-deoxy-2'-methylidene cytidine compound of the general formula (I), its acid addition salt or its hydrate is 2'-deoxy-2'-methylidene cytidine dihydrate,
2'-deoxy-2'-methylidene cytidine hydrochloride 1 /
A compound selected from dihydrate, 2'-deoxy-2'-methylidene-5-fluorocytidine, 2'-deoxy-2'-fluoromethylidenecytidine and 2'-deoxy-2'-ethylidenecytidine. (1) The anticancer composition for oral administration described in (1). (5) The 2′-deoxy-2′-methylidene cytidine compound of the general formula (I), an acid addition salt thereof or a hydrate thereof is 2′-deoxy-2′-methylidene cytidine dihydrate. (1) The anticancer composition for oral administration described in (1).

In the general formula (I), halogen is chlorine, bromine, fluorine or iodine, and alkyl having 1 to 4 carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary butyl. Show. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, or maleate, fumarate, tartrate, succinate, citrate and benzenesulfonic acid. Organic salts such as salt and pamoate are 1/2 as hydrate
Hydrates, monohydrates, 3/2 hydrates, dihydrates and the like can be mentioned. Examples of the 2'-deoxy-2'-methylidene cytidine compound of formula (I), its acid addition salt or its hydrate include 2'-deoxy-2'-methylidene cytidine dihydrate (DMDC2 water). 2'-deoxy-2'-methylidene cytidine hydrochloride hemihydrate, 2 '
-Deoxy-2'-methylidene-5-fluorocytidine (5F-DMDC), 2'-deoxy-2'-fluoromethylidene cytidine (FMdC), 2'-deoxy-
2'-ethylidene cytidine and the like are included.

The sucrose fatty acid ester used as an absorption enhancer is generally called a sugar ester and is a safe substance which is widely used as a food additive. The sucrose fatty acid ester used in the present invention is preferably a fatty acid having 8 to 25 carbon atoms, and may be naturally obtained or synthetically obtained, but preferably, naturally obtained. Momo is used. As the fatty acid, there are linear and branched ones,
A linear one is preferably used. Fatty acids preferably used are caproic acid, capric acid, myristic acid, stearic acid, palmitic acid, lauric acid, oleic acid and the like. There are three primary alcohols in sucrose, and one fatty acid (monoester type), two fatty acid (diester type), and three fatty acid (triester type) linked to each other. Monoester, diester, It may be a mixture of triesters or a mixed ester of 2 to 3 kinds of the above fatty acids. In the present invention, the higher the monoester type ratio, the better the oral absorbability. That is, HL
It was revealed by the present invention that the higher the B value, especially the HLB value of about 10 to 20 is, the better the oral absorption promoting property is. Specifically, for example, Ryoto Sugar Ester S-1170, S-1570, S-1670, P-1570 and P-1570 manufactured by Mitsubishi Kasei Foods Co., Ltd.
-1670, OWA-1570, Daiichi Kogyo Seiyaku Co., Ltd.
DK ester F-110, F-140, F-16
0, SS and the like. Further, sucrose fatty acid ester and HLB value other than about 10 to 20, for example, ryote sugar ester S-970, the same LWA-.
It is also possible to prepare and use 1570 and the like in a mixture of two or more kinds so that the HLB value becomes about 10 to 20. The sucrose fatty acid ester can be used in a weight ratio of 0.1 to 20 times with respect to the 2'-deoxy-2'-methylidene cytidine compound of the general formula (I), preferably 0.5 to. Although it is 10 times, it is not limited to this and can be set as appropriate. In the composition of the present invention, the compound of general formula (I) is about 5 to 500 m in one preparation.
g included.

The anticancer composition for oral administration of the present invention is used after being formulated into a liquid preparation such as syrup and suspension, and a solid preparation such as granules, fine granules, capsules and tablets. However, solid formulations are more preferred. The above-mentioned preparation can be manufactured according to a conventional method. For example, syrups and suspensions can be obtained by dissolving or suspending the compound of general formula (I) and sucrose fatty acid ester in water or an appropriate aqueous solution (hydroxypropylmethylcellulose solution, carboxymethylcellulose solution, etc.). Granules and fine granules are prepared by mixing the compound of general formula (I) and sucrose fatty acid ester in powder form, and if necessary, adding excipients such as sucrose and lactose, and a binder such as hydroxypropylmethylcellulose and kneading. It is produced by granulating with an extrusion granulator equipped with a screen having a diameter of 0.5 to 1 mm, drying and then sieving and classifying. Capsules can be obtained by filling capsules with the powder, granules or fine granules obtained as described above. Tablets are auxiliary components usually used in a mixture of the compound of general formula (I) and sucrose fatty acid ester, for example, excipients such as lactose, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Add a disintegrating agent such as a binder, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, and knead and granulate by wet granulation method or dry granulation method. Light anhydrous silicic acid, magnesium stearate, etc. Of lubricant,
It can be obtained by tableting. Further, the tablets can be made into sugar-coated tablets and film-coated tablets according to a conventional method.

[0009]

The composition of the present invention remarkably improves the absorbability from the digestive tract by incorporating the compound of the general formula (I) useful as a carcinostatic agent in a sucrose fatty acid ester. . In particular, since the composition has improved oral absorbability at high doses of the compound of general formula (I), it has a high bioavailability and is given more excellent characteristics as an internal-use cancer drug. Moreover, sucrose fatty acid ester is a safe substance widely used as a food additive, and is practically desirable. The composition of the present invention enables oral administration of a compound of the general formula (I) such as DMDC dihydrate, and is useful for the treatment or prevention of solid tumors or the like, home treatment, maintenance therapy after treatment, etc. Easy to use. About 50 to 500 mg of the active ingredient can be administered per day for an adult, but the dose may be increased appropriately.

[0010]

The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Example 1 6.9 mg of 2'-deoxy-2'-methylidene cytidine dihydrate and a sucrose fatty acid ester having an HLB value of 19 (the bound fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition Ratio is about 100 monoesters
% (Having a composition ratio of 4.0%), 0.8 ml of 0.5% hydroxypropylmethylcellulose aqueous solution is added and dissolved to prepare an aqueous solution.

Example 2 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 15 (boundary fatty acid: about 70% stearic acid, palmitic acid: about 30%)
%, And the ester composition ratio is about 75% monoester and about 25% ditriester) 90 mg
Then, 5 ml of 0.5% aqueous solution of hydroxypropylmethyl cellulose is added and dissolved to obtain an aqueous solution.

Example 3 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 11 (boundary fatty acid: about 70% stearic acid, palmitic acid: about 30%)
%, The ester composition ratio is about 50% monoester and about 50% ditriester) 90 mg
Then, 5 ml of 0.5% aqueous solution of hydroxypropylmethyl cellulose is added and dissolved to obtain an aqueous solution.

Example 4 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 16 (boundary fatty acid: about 20% stearic acid, palmitic acid: about 80%)
%, The ester composition ratio is about 80% monoester and about 20% ditriester) 90 mg
Then, 5 ml of 0.5% aqueous solution of hydroxypropylmethyl cellulose is added and dissolved to obtain an aqueous solution.

Example 5 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 16 (bound fatty acid: about 70% stearin, palmitic acid: about 30%)
The ester composition ratio is about 75% monoester and about 25% ditriester) 90 mg
Then, 5 ml of 0.5% aqueous solution of hydroxypropylmethyl cellulose is added and dissolved to obtain an aqueous solution.

Example 6 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 19 (boundary fatty acid: about 70% stearic acid, palmitic acid: about 30%)
%, And the ester composition ratio is 30 mg (having a composition ratio of about 100% monoester), and 5 ml of 0.5% aqueous solution of hydroxypropylmethylcellulose is added and dissolved to obtain an aqueous solution.

Example 7 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 19 (boundary fatty acid: about 70% stearic acid, palmitic acid: about 30%)
%, And the ester composition ratio is 90% (having a composition ratio of about 100% monoester), and 5 ml of a 0.5% aqueous solution of hydroxypropylmethylcellulose is added and dissolved to form an aqueous solution.

Example 8 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 19 (boundary fatty acid: about 70% stearic acid, palmitic acid: about 30%)
%, And the ester composition ratio is 150 mg (having a composition ratio of about 100% monoester), and 5 ml of a 0.5% aqueous solution of hydroxypropylmethylcellulose is added and dissolved to obtain an aqueous solution.

Example 9 2'-deoxy-2'-methylidene cytidine dihydrate 3
0 mg and a sucrose fatty acid ester having an HLB value of 19 (boundary fatty acid: about 70% stearic acid, palmitic acid: about 30%)
%, And the ester composition ratio is 300 mg (having a composition ratio of monoester of about 100%), and 5 ml of 0.5% hydroxypropylmethylcellulose aqueous solution is added and dissolved to obtain an aqueous solution.

Example 10 2'-deoxy-2'-methylidene cytidine dihydrate 1
1 part by weight, 1 part by weight of a sucrose fatty acid ester having an HLB value of 19 (the bound fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 100% monoester). After adding 2 parts by weight of sucrose and 0.2 part by weight of hydroxypropylmethylcellulose as a binder, after kneading, granulate with an extrusion granulator equipped with a screen having a diameter of 1 mm, and dry at a temperature of 30 ° C. or lower, Sift and classify to obtain granules.

Example 11 2'-deoxy-2'-methylidene cytidine dihydrate 1
By weight, sucrose fatty acid ester having an HLB value of 16 (boundary fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 75% monoester and about 25% ditriester. ) 3 parts by weight, and further 2 parts by weight of low-substituted hydroxypropylcellulose are added, and 0.2 parts by weight of hydroxypropylmethylcellulose is used as a binder, and after kneading and granulation, the prepared granules are filled into capsules.

Example 12 2'-deoxy-2'-methylidene cytidine dihydrate 1
Parts by weight, sucrose fatty acid ester having an HLB value of 11 (boundary fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 50% monoester and about 50% ditriester. ) 2 parts by weight, and further 8 parts by weight of lactose are added, and 0.2 part by weight of hydroxypropyl cellulose is used as a binder. After kneading, the diameter is 0.5 mm.
Granulate with an extrusion granulator equipped with a screen of 3
It is dried at a temperature of 0 ° C. or lower and sieved to obtain fine granules.

Example 13 2'-deoxy-2'-methylidene cytidine dihydrate 1
Parts by weight, sucrose fatty acid ester having an HLB value of 16 (combined fatty acid: about 70% stearic acid, about 30% palmitic acid)
And the ester composition ratio is about 80% monoester and about 20% ditriester) 5 parts by weight,
Further, 2 parts by weight of low-substituted hydroxypropyl cellulose is added, and 0.2 parts by weight of polyvinylpyrrolidone is used as a binder, and after kneading and granulating, the manufactured particles are filled in a capsule.

Example 14 2'-deoxy-2'-methylidene cytidine dihydrate 1
1 part by weight, 1 part by weight of a sucrose fatty acid ester having an HLB value of 19 (the bound fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 100% monoester). 0.2 parts by weight of lactose,
0.8 parts by weight of microcrystalline cellulose is added, 0.2 parts by weight of hydroxypropylmethyl cellulose is used as a binder, and the mixture is kneaded, crushed, dried and sieved (24 mesh) to obtain a granulated product. Next, magnesium stearate is added, mixed and compressed to obtain tablets.

Example 15 2'-deoxy-2'-methylidene cytidine dihydrate 1
By weight, sucrose fatty acid ester having an HLB value of 16 (boundary fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 75% monoester and about 25% ditriester. ) 0.5 parts by weight, and further 1 part by weight of powdered sugar are added, and 0.2 parts by weight of hydroxypropyl cellulose is kneaded as a binder, and then crushed,
Dry and sieve (24 mesh) to obtain a granulated product. Then, 1 part by weight of carboxymethyl cellulose calcium,
Magnesium stearate is added, mixed and compressed to obtain tablets.

Example 16 2'-deoxy-2'-methylidene cytidine dihydrate 1
Parts by weight, sucrose fatty acid ester having an HLB value of 11 (boundary fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 50% monoester and about 50% ditriester. ) 2 parts by weight, and further 2 parts by weight of low-substituted hydroxypropylcellulose are added, and 0.2 parts by weight of hydroxypropylmethylcellulose is kneaded as a binder, crushed, dried and sieved (24 mesh) to produce Get the granules. Next, magnesium stearate is added, mixed and compressed to obtain tablets.

Example 17 1 part by weight of 2'-deoxy-2'-methylidene cytidine dihydrate, sucrose fatty acid ester having an HLB value of 16 (boundary fatty acid is about 70% stearic acid, palmitic acid about 30%).
And the ester composition ratio is about 80% monoester and about 20% ditriester) 3 parts by weight,
Furthermore, 6 parts by weight of low-substituted hydroxypropylcellulose and magnesium stearate are mixed, tableted by a conventional method, then crushed and sieved. The granules thus produced are taken and tableted again to obtain tablets.

Example 18 2'-deoxy-2'-methylidene cytidine dihydrate 1
1 part by weight, 1 part by weight of a sucrose fatty acid ester having an HLB value of 19 (the bound fatty acid is about 70% stearic acid and about 30% palmitic acid, and the ester composition ratio is about 100% monoester). 8 parts by weight of lactose is added, and 0.2 part by weight of low-substituted hydroxypropylcellulose is used as a binder to produce granules by wet granulation. The obtained granules are put into a coating pan and spray-coated by a conventional method using an alcohol solution of Eudragit L so as to increase the weight of the granules by 10%.
Obtain an enteric formulation. By performing the same treatment as in Examples 1 to 18, 2'-deoxy-2'-methylidene cytidine hydrochloride hemihydrate, 2'-deoxy-2'-methylidene-5-fluorocytidine, 2 '-Deoxy-2'-fluoromethylidene cytidine or 2'-deoxy-2'
It is possible to produce a composition containing ethylidene cytidine.

[0028]

In order to show the action and effect of the present invention, typical test results for the above examples (compositions of the present invention) will be described. In addition, the following reference example was used as a composition for comparison. Reference Example 1 To 6.9 mg of 2'-deoxy-2'-methylidene cytidine dihydrate, 0.8 ml of 0.5% hydroxypropylmethylcellulose aqueous solution was added and dissolved to obtain an aqueous solution.

Reference Example 2 2'-deoxy-2'-methylidene cytidine dihydrate 6.9 mg and sodium caprate 6.9 mg,
0.8 ml of 0.5% aqueous solution of hydroxypropylmethyl cellulose is added and dissolved to obtain an aqueous solution.

Reference Example 3 2'-deoxy-2'-methylidene cytidine dihydrate 6.9 mg and polyoxyethylene (20) sorbitan monooleate 4.0 mg were added to 0.5% hydroxypropylmethyl cellulose aqueous solution 0.8 ml. Is added and dissolved to form an aqueous solution.

Reference Example 4 6.9 mg of 2'-deoxy-2'-methylidene cytidine dihydrate and polyoxyethylene hydrogenated castor oil 4.
To 0 mg, 0.8 ml of 0.5% hydroxypropylmethylcellulose aqueous solution is added and dissolved to give an aqueous solution.

Reference Example 5 2'-deoxy-2'-methylidene cytidine dihydrate 3
To 0 mg, 5 ml of a 0.5% aqueous solution of hydroxypropylmethylcellulose was added and dissolved to give an aqueous solution.

Reference Example 6 2'-deoxy-2'-methylidene cytidine dihydrate 6.9 mg and sodium oleate 6.9 mg,
0.8 ml of 0.5% aqueous solution of hydroxypropylmethyl cellulose is added and dissolved to obtain an aqueous solution.

Reference Example 7 2'-deoxy-2'-methylidene cytidine dihydrate 6.9 mg and sodium lauryl sulfate 4.0 mg
0.8 ml of a 0.5% aqueous solution of hydroxypropylmethyl cellulose is added to and dissolved into an aqueous solution.

Test 1: in situ loop test The aqueous solutions obtained in Example 1 and Comparative Examples 1 to 4, 6 and 7 were used as specimens. As a test animal, a 7-8 week-old male Sprague Dawley rat (body weight: 200-25
0 g) was used in 4 animals per group. Under anesthesia with light ether, each rat was placed on the duodenum with 10 cm long loops 1 and 10.
A loop 2 having a length of cm was prepared. Two of the four mice in one group were provided with DMDC dihydrate alone (Reference Example 1) for loop 1, and DMDC dihydrate + absorption enhancer for loop 2 (Example 1,
Reference Examples 2 to 4, 6 and 7) and DMDC dihydrate + absorption promoter (Example 1, Reference Examples 2 to 2) in the remaining two loops 1.
4, 6, 7) and loop 2 were administered with DMDC dihydrate alone (Reference Example 1). The remaining amount in each loop was calculated 2 hours after administration, and the absorption rate was calculated from the difference between the dose in the loop and the remaining amount in the loop. The results are shown in Table 1. The absorption rate is shown as the average value ± standard deviation.

[0036]

[Table 1]

From the above test results, in the formulation for oral administration containing sucrose fatty acid ester of the present invention (Example 1), DMDC dihydrate was compared with the formulation containing no absorption enhancer (Reference Example 1). It can be seen that the absorption rate of is greatly improved. In addition, in the preparations containing conventional absorption enhancers (Reference Examples 2 to 4), no improvement in absorption of DMDC dihydrate was observed. On the other hand, a remarkable improvement in the absorption rate was observed for sodium oleate, and especially sodium lauryl sulfate, but the formulation containing these was inferior in the urinary excretion rate as shown in the following Test Example 2, and there was a problem.

Test 2: Absorption and excretion test Seven to eight-week-old male Sprague Dawley rats (body weight: 200 to 250 g) fasted overnight as a test animal were grouped in 4 groups.
Used in animals. Each rat was orally administered with the preparation of the present invention obtained in Examples 2 to 9 as a test preparation and the preparation obtained in Reference Example 5 as a control preparation. Urine was collected from each rat up to 24 hours after administration, and the DMDC dihydrate concentration in the urine was measured by high performance liquid chromatography.
The urinary excretion rate of DMDC dihydrate was calculated by the following formula. The results are shown in Table 2. The urinary excretion rate is shown as the average value ± standard deviation.

[0039]

[Table 2]

From the above-mentioned test results, the oral administration preparations (Examples 2 to 9) to which the absorption enhancer (sucrose fatty acid ester) of the present invention was added were classified as those without the absorption enhancer (Reference Example 5). By comparison, it can be seen that the urinary excretion rate of DMDC dihydrate is greatly improved. Instead of sucrose fatty acid ester, sodium oleate (composition ratio x 1) and sodium lauryl sulfate (composition ratio x 0.
When a similar absorption and excretion test was carried out using 2), no remarkable effect was observed. Sodium oleate: 51.6 ± 6.3 (%) Sodium lauryl sulfate: 46.4 ± 7.6 (%) From various experimental results including these test examples, DMDC2 was prepared by blending sucrose fatty acid ester. Absorption rate from gastrointestinal tract is improved in the formulation with high content of hydrate,
The urinary excretion rate was also greatly improved. Therefore, the composition of the present invention is useful as a DMDC dihydrate formulation with improved oral absorption.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Shigeyuki Shibata, 955, Shoji, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture, Central Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd.

Claims (5)

[Claims] 1. A general formula: (In the formula, R represents hydrogen or halogen, and R ¹ and R ² are the same or different and each represents hydrogen, halogen or carbon number 1 to 4;
Is alkyl. 2'-deoxy- represented by
A carcinostatic composition for oral administration comprising a 2'-methylidene cytidine compound, an acid addition salt thereof or a hydrate thereof and sucrose fatty acid ester. 2. The anticancer composition for oral administration according to claim 1, which contains a sucrose fatty acid ester having an HLB value of about 10 to 20. 3. The oral composition according to claim 1, wherein the content of the sucrose fatty acid ester is 0.1 to 20 times the weight of the compound of the general formula (I), its acid addition salt or its hydrate. Anticancer drug composition for administration. 4. 2'-deoxy-2'- of the general formula (I)
Methylidene cytidine compound, its acid addition salt or its hydrate is 2'-deoxy-2'-methylidene cytidine dihydrate, 2'-deoxy-2'-methylidene cytidine hydrochloride hemihydrate 2'-deoxy-2'-methylidene-
The anticancer composition for oral administration according to claim 1, which is a compound selected from 5-fluorocytidine, 2'-deoxy-2'-fluoromethylidene cytidine and 2'-deoxy-2'-ethylidene cytidine. 5. 2'-deoxy-2'- of the general formula (I)
The anticancer composition for oral administration according to claim 1, wherein the methylidene cytidine compound, its acid addition salt or its hydrate is 2'-deoxy-2'-methylidene cytidine dihydrate.