JPH0436237A - Composite antitumor preparation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Industrial applications The present invention relates to an anti-tumor complex formulation.

Conventional technology It has been confirmed that when uracil is used in combination with 5-fluorouracil (5-FU) derivatives, it synergistically enhances the antitumor activity of 5-FU derivatives, and the combination of tegafur and uracil is superior. It is frequently used as an oral preparation with antitumor effects, such as gastric soluble capsules. However, tegafur has the disadvantage that major side effects include gastrointestinal symptoms such as loss of appetite, nausea, vomiting, diarrhea, and stomatitis.

Problems to be Solved by the Invention An object of the present invention is to provide a clinically useful combination drug of uracil and tegafur with reduced side effects.

Means for Solving the Problems The present inventors have developed a method to reduce gastrointestinal side effects such as anorexia, nausea, vomiting, diarrhea, and stomatitis, and maintain a high blood concentration of 5-FtJ, which is an active metabolite of tegafur. We have been conducting intensive research with the aim of developing an antitumor agent containing uracil and tegafur that can be used to treat cancer.

As a result, when a combination drug of tegafur and uracil is made into an enteric-coated preparation, uracil does not necessarily reach a sufficient blood concentration, and the blood concentration of 5-FU, the active metabolite of tegafur, decreases. was recognized.

As a result of further research, the present inventors have determined that 5-FU can be reduced in the blood by making a combination preparation of tegafur and uracil into a composite preparation consisting of a gastric-soluble preparation containing uracil and an enteric-coated preparation containing tegafur. It was discovered that a clinically extremely good preparation that could maintain a high intermediate concentration and reduced side effects could be obtained, and the present invention was thus completed.

That is, the present invention relates to an antitumor composite preparation characterized by comprising a gastric composition containing uracil and an enteric composition containing tegafur.

The gastric soluble composition of uracil included in the composite preparation of the present invention is
It can be made into various known formulations, such as solid preparations for oral administration such as tablets, granules, capsules, fine granules, and powders. These can be manufactured according to known and commonly used formulation methods. For example, after adding excipients to uracil, and if necessary, disintegrants, binders, lubricants, etc., they can be manufactured according to conventional methods. can. Known excipients, disintegrants, binders, and lubricants can be used, and they may be used alone or in combination of two or more. Specifically, excipients include lactose, sucrose, glucose, sucrose, starch, crystalline cellulose, etc., and disintegrants include carboxymethyl cellulose or its calcium salt, low-substituted hydroxypropyl cellulose, starch, hydroxypropyl starch, and dextrin. etc.,
As a binder, methylcellulose, ethylcellulose,
Hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinylpyrrolidone, hydroxypropylcellulose, etc. can be used, and as the lubricant, talc, stearic acid, stearate, waxes, light silicic anhydride, etc. can be used. Furthermore, if necessary, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, etc. may be used as a coating agent to increase the strength of the granules.

A preferred pharmaceutical form of the gastric soluble composition containing uracil includes granules.

The gastric soluble composition containing uracil used in the present invention is preferably prepared by blending uracil with crystalline cellulose. As the crystalline cellulose, various commercially available products can be used, and these can be used alone or in combination.

The amount of crystalline cellulose used is preferably 10 to 50%, more preferably 20 to 40% (by weight) based on uracil. Furthermore, by using crystalline cellulose and the above-mentioned disintegrant in combination, a more useful composition can be obtained. In this case, the amount of disintegrant used is desirably within 60% of the amount of crystalline cellulose.

In the gastric soluble composition containing uracil used in the present invention,
The amount of uracil to be blended is preferably 20 to 90%, more preferably 40 to 85% (heavy) based on the entire gastric soluble composition.

The enteric composition containing tegafur to be incorporated into the composite preparation of the present invention can be in various known formulation forms,
For example, it can be made into solid preparations for oral administration such as tablets, granules, capsules, fine granules, and powders. These can be manufactured by known and commonly used formulation methods, for example,
After adding an excipient, an enteric coating agent, a disintegrant, a binder, a lubricant, etc. as necessary to tegafur, it can be manufactured according to a conventional method. Known excipients, disintegrants, binders, and lubricants can be used, and they may be used alone or in combination of two or more (specifically, the above-mentioned Those listed above can be used. Examples of enteric coating agents include hydroxypropyl methyl cellulose phthalate, hydroquine propyl methyl cellulose acetate sacnate, carboxin methyl ethyl cellulose, methacrylic acid copolymer L1, methacrylic acid copolymer LD, and the like.

Preferred pharmaceutical forms of enteric-coated compositions containing tegafur include granules.

In the enteric-coated composition containing tegafur used in the present invention, the amount of tegafur to be blended is as follows with respect to the entire enteric-coated composition:
Preferably 10-70%, more preferably 30-65%
(weight).

The composite preparation of the present invention can be obtained by blending or formulating the above-mentioned gastrosoluble composition containing uracil and the enteric composition containing tegafur.

Although the ratio of the enteric composition containing tegafur and the gastric composition containing uracil in the composite preparation of the present invention varies depending on the need, it is generally the same as the amount of tegafur in the enteric composition. It is determined by the amount of uracil in the gastric soluble composition, and 0.0.
It is preferable to use 0.02 to 10 moles, preferably 0.1 to 10 moles.

In the composite preparation of the present invention, each composition can be administered separately, but it is also possible to mix the respective compositions in advance and administer them after formulating them into various dosage unit forms. Examples of dosage unit forms include solid preparations for oral administration such as granules, capsules, tablets, fine granules, and powders, or combination preparations thereof. These can be formulated according to conventional methods. When preparing such a dosage unit form, the above-mentioned excipients, disintegrants, binders, lubricants, etc. may be added as necessary, and then the preparation may be carried out according to a conventional method.

The amount of tegafur contained in the composite preparation of the present invention is 50 to 250 per unit dosage form! IIg is preferred.

The composite preparation of the present invention thus obtained can be used as an antitumor agent, and the dosage varies depending on the symptoms, body weight, age, sex, etc. ~30mg/k
g, and this can also be administered in 1 to 4 divided doses on -day.

Example Examples and experimental examples of the present invention are shown below.

Production example 1: Uracil gastric soluble granules Uracil 224 mg Crystalline cellulose 53B carboxymethyl cellulose calcium salt 16 mg Polyoxyl stearate 40 4 mg Hydroxypropyl cellulose 3 mg total
300 mg of uracil, crystalline cellulose, carboxymethyl cellulose calcium salt, polyoxyl stearate 40, and hydroxypropyl cellulose solution were mixed in the above proportions and extrusion granulation was performed to prepare uracil gastric soluble granules (granules 1).

Production example 2: Uracil gastric soluble capsules Uracil
145II 1g lactose
153mg crystalline cellulose 40111g hydroxypropylcellulose 10mg magnesium stearate in 2B1 capsule
350D uracil, lactose, crystalline cellulose and hydroxypropyl cellulose were mixed in the above proportions, water was added and extrusion granulated, after drying, magnesium stearate was added and filled into hard gelatin capsules (
Capsules 1).

Production example 3: Uracil gastric soluble fine granules Uracil 250mg lactose
120mg crystalline cellulose 80a+g cornstarch 45mg hydroxypropyl methylcellulose 5mg total
500a+g uracil, lactose, crystalline cellulose, cornstarch and hydroxypropyl methylcellulose were mixed in the above proportions, water was added and granulated to prepare uracil gastric soluble fine granules (fine granules 1).

Production example 4: Uracil gastric soluble tablet Uracil 75mg lactose
55mg crystalline cellulose 20mg magnesium stearate 2mg talc
3mg methylcellulose
10mg total
Mix 165mg of uracil, lactose, crystalline cellulose and methylcellulose in the above ratio, add water to granulate it, dry it, mix it with talc and magnesium stearate, and compress it to make 165mg of heavy fi, 7ro in diameter.
m tablets (tablet 1).

Production example 5: Tegafur enteric-coated granules Tegafur 100a+g Crystalline cellulose 15mg Carboxymethylcellulose calcium salt 20mg Polyoxyl stearate 40 5mg Hydroxypropylcellulose iomg Methacrylic acid copolymer L D 50mg total
After preparing granules in the same manner as in Production Example 1, they were coated with methacrylic acid copolymer LD and treated with tegafur enteric-coated granules (Granules 2).
was prepared.

Production example 6: Tegafur enteric-coated capsules Tegafur
70mg crystalline cellulose
100g Lactose 113D Ethylcellulose 5mg Magnesium Stearate 2mg Methacrylic Acid Copolymer L 50mg in 1 capsule
250mg tegafur, crystalline cellulose,
Lactose and ethyl cellulose were mixed in the above proportions, water was added, extrusion granulated, dried, coated with methacrylic acid copolymer, magnesium stearate was added, and then filled into hard gelatin capsules (Capsule 2). ).

Production example 7: Tegafur enteric-coated fine granules Tegafur 400mg lactose
300mg cornstarch 90mg hydroxypropyl methylcellulose LOmg hydroxypropyl methylcellulose acetate succinate) 200mg total
1000 mg was granulated in the same manner as in Production Example 3, dried, and coated with hydroxypropyl methylcellulose acetate succinate to prepare tegafur enteric-coated fine granules (fine granules 2).

Production example 8: Tegafur enteric coated tablet Tegafur 100mg lactose
50mg Crystalline cellulose 20mg Magnesium stearate 2mg Hydroquinepropyl starch 8[[1g Hydroquinepropyl methyl cellulose phthalate 40mg Total 220D Compressed in the same manner as Production Example 4, weight 180mg, diameter 8
A tegafur enteric-coated tablet (tablet 2) was prepared by molding a tablet of 1.0 mm in size and then coating it with hydroxypropyl methylcellulose phthalate.

Reference Production Example 1 Enteric-coated granules of uracil (granules 3) were prepared in the same manner as in Production Example 1 by mixing the ingredients in the following proportions.

Uracil 22401g Crystalline cellulose 17mg Carboxymethyl cellulose calcium salt 20B Polyoxyl stearate 40 4mg Lactose
12+ag Hydroxypropyl cellulose 3a+g Methacrylic acid copolymer L D 80mg total
360 mg Example 1: Composite granules 1300 mg of granules and 2200 n1 g of granules were mixed to prepare composite granules A (product of the present invention).

Example 2: Composite capsule A (product of the present invention) was prepared by mixing 1150 mg of composite capsule granules and 2100 ωg of granules and filling them into hard gelatin capsules.

Example 3: Composite tablet granule 2 10hg uracil 10hg crystalline cellulose 28mg magnesium stearate 2mg total
230 mg Granule 2, uracil, crystalline cellulose, and magnesium stearate were mixed in the above ratio and compressed to prepare a composite tablet A (product of the present invention) having a weight of 230 mg and a diameter of 9 mm.

Comparative Example 1 Enteric-coated granules of uracil (granules 3) 36 g and enteric-coated tegafur granules (granules 2) 20 DII 1 g
were mixed to obtain enteric-coated composite granules B (comparative product).

Experimental Example 1 Composite granule A of the present invention and composite granule B of the comparative product were orally administered to Peagle-sized animals, blood was collected over time, and tegafur, uracil, and 5-5, which is an active metabolite of tegafur, were administered orally to a Peagle-sized animal, and blood was collected over time.
The plasma concentration of FU was measured. The results are calculated as pharmacokinetic parameters (AUC (area under the blood concentration curve), Cmax
(maximum blood concentration)) and are shown in Tables 1 and 2, respectively.

Table 1 (AUG (μg-hr/ll1l)) 2nd
Table (Cmax (μg/ml)) Uracil and 5-F
The AUC and Cmax of U showed significantly lower values in composite granule B containing enteric-coated uracil granules, and a decrease in blood concentration was observed.

On the other hand, in composite granules A containing gastric soluble uracil granules, the blood concentration of 5-FU was maintained at a high level and very good clinical results were obtained.

Experimental Example 2 A male patient aged 77 years old and weighing 45 kg underwent surgery for laryngeal cancer.
Immediately after administering NFT (registered trademark), a preparation containing both uracil and tegafur in a gastric solvent, for two weeks, the composite granules A of the present invention were administered for two weeks, and the type and degree of side effects were observed.

In both cases, the daily dose is 600 II as the amount of tegafur.
The dose was 1 g/body, and it was orally administered in 3 doses on consecutive days.

On the 100th day after starting administration of NFT, anorexia developed, and on the 144th day thereafter, the symptoms worsened, and the patient was left with no meals at all.

Furthermore, on the 122nd day, nausea and vomiting occurred.

However, after switching to the composite granules of the present invention, improvement in nausea and vomiting was observed from the second day, and improvement in anorexia was observed on the third day, which completely disappeared on the fourth and seventh days, respectively. There was no recurrence of the above symptoms during administration of the invention composite granules.

Experimental Example 3 A male patient aged 59 years old and weighing 49 kg after surgery for hypopharyngeal cancer was administered composite granules A of the present invention for 2 weeks, followed by administration of NFT for 2 weeks, and then administered composite granules of the present invention again for 2 weeks. The type and degree of side effects were observed. In both cases, the daily dose is 60 tegafur.
The dose was 0 mg/body, and the drug was orally administered in three doses on consecutive days.

No side effects were observed during administration of the first composite granule of the present invention. After switching to NFT, anorexia, nausea, and vomiting developed, and these symptoms continued on the 144th day. However, after switching to the composite granules of the present invention again, the nausea and vomiting completely disappeared, and the frequency and severity of anorexia also decreased considerably.

Effects of the Invention The composite preparation of the present invention, which contains a gastrosoluble composition containing uracil and an enteric composition containing tegafur, can maintain a high blood concentration of 5-FU, an active metabolite, and has very few side effects. This is extremely useful clinically. Therefore, the composite preparation of the present invention is useful as an antitumor agent in the treatment of tumors.

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Claims (2)

[Claims] (1) An antitumor composite preparation comprising a gastric composition containing uracil and an enteric composition containing tegafur. (2) The composite preparation according to claim 1, wherein the gastric soluble composition containing uracil contains crystalline cellulose.