HK1115306A - ANTICANCER DRUG CONTAINING α, α, α-TRIFLUOROTHYMIDINE AND THYMIDINE PHOSPHORYLASE INHIBITOR - Google Patents

Description

Anticancer agent comprising alpha, alpha-trifluorothymidine and thymidine phosphorylase inhibitor

Technical Field

The present invention relates to an anticancer agent obtained by using a combination of α, α, α -trifluorothymidine (FTD) and Thymidine Phosphorylase Inhibitor (TPI), which is a cancer therapeutic agent having a strong cancer therapeutic effect.

Background

α, α, α -trifluorothymidine (FTD, see the following structural formula) is a nucleic acid derivative synthesized by Heidelberger et al in which the methyl group at the 5-position of thymidine is substituted with a trifluoromethyl group (non-patent documents 1 and 2).

Unlike the Fluorouracil (FU) -based antitumor agent widely used in clinical applications, FTD does not act on RNA but phosphorylates it with intracellular thymidine kinase to form monophosphoryl trifluorothymidine monophosphate (F)₃TMP). The F₃TMP binds to Thymidylate Synthase (TS) and exhibits a DNA synthesis inhibitory effect (non-patent documents 3 and 4). Although it is considered that TS inhibition is a main action of FU-based antitumor agents widely used in clinical applications, it is known that in recent years, patients have low susceptibility to FU-based antitumor agents (non-patent documents 5 to 7). On the other hand, since FTD is incorporated into DNA, its antitumor effect is distinguishable from that of FU-based antitumor agents, and it is considered to be a clinically effective antitumor agent that can overcome the above-mentioned problems. FTD was tried in 1970 s for clinical trials, but it was pointed out that there are problems with FTD itself when administered intravenously: decomposition of FTD by Thymidine Phosphorylase (TP) in an organism and the half-life of FTD in blood caused thereby are shortened to a very short time of about 12 minutes (non-patent document 8). Further, although the tumor reduction effect in patients was observed by intravenous administration every 3 hours, this administration method not only had problems in general use but also found blood toxicity and digestive tract toxicity, and further,even patients who find a reduction in tumor size do not necessarily have a problem of a long life expectancy (non-patent document 9).

Accordingly, the present applicant has found that 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride (see the following structural formula) as a Thymidine Phosphorylase Inhibitor (TPI) for inhibiting the decomposition of FTD, which should be orally administered for maintaining the concentration of FTD in blood and improving the versatility, and developed a cancer therapeutic agent (TAS-102) in which FTD and the TPI are mixed at a molar ratio of 1: 0.5 (patent document 1 and non-patent document 10).

The formulation was tested in the USA in phase I clinical trials, starting with 1 oral administration for 1 day,

the concentration of FTD in blood was maintained, and it was confirmed that the compounding agent was a drug that can be administered orally. But do not

Thus, the compounding agent has not yet satisfied the clinical effect of cancer treatment.

Non-patent document 1: j.am.chem.soc., 84: 3597-3598, 1962

Non-patent document 2: med. chem., 7: 1-5, 1964

Non-patent document 3: biochemistry, 33: 15086 to 15094, 1994

Non-patent document 4: mol. pharmacol, 1: 14 to 30, 1965

Non-patent document 5: clin oncol, 12: 2640-2647, 1994

Non-patent document 6: clin oncol., 14: 176-182, 1996

Non-patent document 7: clin oncol., 21: 815 to 819, 2003

Non-patent document 8: cancer res, 32: 247 to 253, 1972

Non-patent document 9: cancer chemother, rep., 55: 205 to 208, 1971

Non-patent document 10: international Journal of Oncology 25: 571 to 578 and 2004

Patent document 1: japanese patent No. 3088757

Disclosure of Invention

Accordingly, an object of the present invention is to provide a cancer therapeutic agent having higher efficacy.

The inventor finds that: the dosage scheme of the compounding agent is changed, the oral administration is carried out for 2-4 times in 1 day on human, and 1 day 100mg/m is needed when 1 time administration is carried out for 1 day²(FTD equivalent) is unexpectedly administered in an amount of 20 to 80mg/m for 1 day²Can achieve a remarkable anticancer effect with a low dose, and thus the present invention has been completed.

That is, the present invention provides a therapeutic agent for cancer, which is a composition (hereinafter referred to as TAS-102) comprising FTD and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride (hereinafter referred to as TPI-1) in a molar ratio of 1: 0.5, and the amount of FTD converted for the therapeutic agent is 20 to 80mg/m²The dose per day is administered orally 2 to 4 times per day in 1 day.

The present invention also provides a composition comprising α, α, α -trifluorothymidine (FTD) and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride in a molar ratio of 1: 0.5, wherein the amount of FTD converted in the production process is 20 to 80mg/m²The dose per day is 1 day, 2-4 times, and is used in a cancer therapeutic agent for oral administration.

The present invention also provides a method for treating cancer, which comprises mixing a composition comprising α, α, α -trifluorothymidine (FTD) and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride in a molar ratio of 1: 0.5 in an amount of 20 to 80mg/m in terms of FTD²The daily dose is 1 day and 2-4 timesThe administration is oral.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the cancer therapeutic agent of the present invention, although the total dose for 1 day is lower than that in the case of 1 administration for 1 day, a better cancer therapeutic effect can be achieved.

Drawings

FIG. 1 is a graph showing the comparison between the therapeutic effect of a digestive cancer in the case of orally administering 1 time per day and 3 times per day a TAS-102 preparation containing FTD and TPI-1 and the therapeutic effect of a digestive cancer in the case of orally administering 1 time per day (PD: development, SD: stabilization, MR: micro-effect, PR: partial effect). The vertical axis represents each patient, and the horizontal axis represents the number of treatment sessions. The treatment course comprises 1 week of administration for 5 days, 2 days of withdrawal, 2 weeks of withdrawal, and 4 weeks of total treatment. In addition, the withdrawal period may be gradually increased according to the health status, the side effect status, and the like of the patient.

FIG. 2 is a graph comparing the therapeutic effects of the TAS-102 formulation containing FTD and TPI-1 on breast cancer when orally administered 1 day 2 times (PD: development, SD: stabilization, MR: micro-effect, PR: partial effect). The vertical axis represents each patient. The horizontal axis represents the number of treatment sessions. The treatment course is as described above.

Detailed Description

The compositions of the present invention are compositions containing FTD and TPI-1 in a molar ratio of 1: 0.5. Wherein FTD is alpha, alpha-trifluorothymidine, which is a compound formed by phosphorylation by using intracellular thymidine kinase₃TMP, which is a drug that inhibits DNA synthesis by binding thymidylate synthase and inhibits cancer cell proliferation. On the other hand, TPI-1 is a drug which inhibits thymidine phosphorylase, which is an FTD-degrading enzyme, and thereby prevents inactivation due to FTD degradation.

The composition may be a composition which can be orally administered, and may containA single formulation of both FTD and TPI-1, or a combination of a formulation containing FTD and a formulation containing TPI-1. The form of these preparations includes tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions and the like. These preparations can be prepared by a conventional preparation method generally known in the art using a pharmaceutically acceptable carrier or the like. The dosage of the preparation can be 20-80 mg/m²The medicine is properly split and packaged in a mode of administering 2-4 times in 1 day per day. The packaging method is not particularly limited as long as it is a conventional packaging method generally known in the art, and for example, in the case of tablets, it can be packaged in a moisture-proof and oxidation-resistant packaging material.

When the carrier is formed into a tablet form, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binding agents such as water, ethanol, propanol, corn starch, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, hydroxypropyl methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrating agents such as dried starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, glyceryl monostearate, starch, and lactose; disintegration inhibitors such as white sugar, stearic acid, cacao butter, and hydrogenated oil; absorption promoters such as quaternary ammonium hydroxide and sodium lauryl sulfate; humectants such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.; lubricants such as refined talc, stearate, boric acid powder, polyethylene glycol, and the like. The tablet may be a tablet to which a usual coating is applied as necessary, and examples thereof include a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double-layer tablet, and a multi-layer tablet.

When the carrier is formed into a pill form, for example, excipients such as glucose, lactose, starch, cacao butter, solidified vegetable oil, kaolin, talc and the like; bonding agents such as acacia powder, tragacanth powder, gelatin, and ethanol; disintegrating agents such as laminarin and agar.

Capsules the above-mentioned ingredients are mixed with the various carriers exemplified above according to a conventional method, and the mixture is filled into hard gelatin capsules, soft gelatin capsules, or the like to prepare the capsules.

In the case of producing an oral liquid preparation, an oral liquid, syrup, elixir, etc. can be produced according to a conventional method using a taste-improving agent, a buffer, a stabilizer, a flavoring agent, etc. In this case, examples of the taste-improving agent include white sugar, orange peel, citric acid, tartaric acid, and the like; examples of the buffer include sodium citrate; examples of the stabilizer include tragacanth gum, gum arabic, and gelatin.

The above preparations may further contain, as required, colorants, preservatives, flavors, sweeteners, and other medicinal products.

The composition has an FTD conversion amount of 20-80 mg/m²The dose per day is administered orally 2 to 4 times per day. More preferably, the amount administered in 1 day is 25 to 75mg/m in terms of FTD²More preferably 30 to 75 mg/m/day²A daily dose of 50 to 70mg/m is particularly preferred²Day/day. Wherein the dose to the patient is determined based on the Body Surface Area (BSA) calculated from the height and weight of the patient. The method of calculating the body surface area is appropriately performed according to the race, sex, health condition, symptom, etc. of the patient, and examples thereof include the following calculation formulas 1 to 5, preferably 1 or 2 (a).

The Mosteller formula (see N Engl J Med 1987 Oct 22; 317 (17): 1098(letter))

BSA(m²) Not ([ height (cm) × body weight (kg)]/3600)1/2

The DuBois and DuBois formula (see Arch Int Med 191617: 863-71; J Clin Anesth.1992; 4 (1): 4-10)

(a)BSA(m²) 0.20247 × height (m))^0.725X body weight (kg)^0.425

(b)BSA(m²) 0.007184 x height (cm)^0.725X body weight (kg)^0.425

The Haycock formula (refer to The Journal of petrorics 197893: 1: 62 ~ 66)

BSA(m²) 0.024265 x height (cm)^0.3964X body weight (kg)^0.5378

The Gehan and George formula (see Cancer Chemother Rep 197054: 225 to 35)

BSA(m²) Not equal to 0.0235 x height (cm)^0.42246X body weight (kg)^0.5456

The Boyd format (cf. Minneapolis: unity of Minnesota Press, 1935) BSA (m)²) 0.0003207 x height (cm)^0.3X body weight (grams)^{(0.7285-(0.0188×LOG(grams))}

For example, when the body surface area of a cancer patient having a height of 175cm and a weight of 70kg is calculated by using the calculation formula 1, the calculated body surface area is [175 (cm). times.70 (kg)]/3600)1/2＝1.84(m²). The dosage for the patient is 60mg/m²The dose is 1.84 × 60 to 111mg per day, the total dose per 1 day is set to about 110mg, and the dose is administered in 2 to 4 divided doses.

In the invention, the conversion amount of FTD is 20-80 mg/m²The dose per day is orally administered 2 to 4 times per day 1 day, and more preferably 2 to 3 times per day 1 day. The interval between administration and administration is preferably 6 hours or more.

In the present invention, the 1-week administration schedule may be daily, and from the viewpoint of reducing the burden on the patient, a 1-week administration schedule of 5 days and a 2-day rest schedule are preferred, and a 1-week administration schedule of 5 days and a 2-day rest schedule of 2 weeks are more preferred, and a 2-week repeat administration schedule of 2 weeks and a 2-week rest schedule of 2 weeks are more preferred.

The cancer to be treated with the therapeutic agent for cancer of the present invention is not particularly limited, and examples thereof include esophageal cancer, gastric cancer, liver cancer, gallbladder/bile duct cancer, pancreatic cancer, colon/rectal cancer, head and neck cancer, lung cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, testicular tumor, bone/soft-segment cyst, skin cancer, malignant lymphoma, leukemia, brain tumor, and the like, and preferably malignant solid cancers such as gastric cancer, pancreatic cancer, breast cancer, colon/rectal cancer, head and neck cancer, gallbladder/bile duct cancer, lung cancer, and the like.

According to the present invention, an extremely excellent cancer therapeutic effect can be achieved despite a small dose compared to 1 administration for 1 day. This is because, when the drug is administered 2 to 4 times per 1 day, the amount of FTD incorporated into the target site DNA increases. In addition, the method of the present invention can easily control side effects.

Examples

The present invention will be described in further detail with reference to the following examples, but the present invention is not limited to these examples.

Formulation example 1.

FTD 20.00mg

TPI-1 9.42mg

Lactose 70.00mg

Crystalline cellulose 3.50mg

Magnesium stearate 1.00mg

Talc 1.00mg

Corn starch 3.50mg

Hydroxypropyl methylcellulose 25.00mg

Each tablet is 133.42mg

Tablets were prepared according to the conventional method using the above compounding ratio.

Formulation example 2.

FTD 15.00mg

TPI-1 7.07mg

Lactose 45.00mg

Carboxymethyl cellulose 5.00mg

Magnesium stearate 2.00mg

Titanium oxide 0.50mg

Hydroxypropyl methylcellulose 1.00mg

Polyethylene glycol 40000.50 mg

Each tablet is 85.07mg

Preparing tablets according to the conventional method by adopting the mixing ratio

Formulation example 3.

FTD 30.00mg

TPI-1 14.13mg

Lactose 85.00mg

Corn starch 100.00mg

Hydroxypropyl cellulose 2.50mg

231.63mg each bag

The granules are prepared according to the conventional method by adopting the mixing ratio.

Formulation example 4.

FTD 10.00mg

TPI-1 4.71mg

Lactose 24.00mg

Crystalline cellulose 12.50mg

Magnesium stearate 1.00mg

Each capsule is 52.21mg

The capsules are prepared according to the conventional method by adopting the mixing proportion.

Example 1

TAS-102 was administered to cancer patients in an amount of 100mg/m in terms of FTD²1 oral administration 1 day (test 1) and 70mg/m²And 3 times of oral administration (test 2) on 1 day, the therapeutic effect was examined.

This test is performed on patients with digestive organ cancer who have failed the standard therapy or have not had the therapy, and is evaluated mainly for safety, and corresponds to a clinical phase I test in which the optimum dose (RD) for safe administration is determined without causing side effects in clinical phase II tests performed for each cancer. In this case, the therapeutic effect on the tumor was evaluated if it could be evaluated. The therapeutic effect of a tumor is evaluated by comprehensively evaluating a target lesion (a lesion having a measurable size or larger corresponding to the slice width in CT or the like) and a non-target lesion (all lesions except the target lesion) by referring to RECIST evaluation (Journal of the National Cancer Institute, 2000, Vol 92, No.3, 205 to 216). In this test, PR (partial efficacy) means that the total length-diameter of each target lesion is reduced to 30% or more of the total length-diameter of each target lesion before administration, and the effect is maintained for a certain period (usually 4 weeks) without deterioration of non-target lesions being observed during the period. PD (progression) refers to the case where the sum of the major diameters of the target lesion is increased by more than 20% compared to the smallest sum of the major diameters recorded after the start of the trial, or where an already existing non-target lesion is significantly deteriorated, or a new lesion is found. SD (stable) means that the tumor shrinkage is insufficient as PR, the tumor growth is stopped and no deterioration is observed, as PD is insufficient. MR (micro-effect) is a disease condition in which the tumor is kept at an effect similar to that of tumor reduction (reduction of about 15%) or a therapeutic effect corresponding to PR is temporarily exhibited, although the tumor reduction is less than 300%.

The results are shown in FIG. 1. In FIG. 1, test 1 is a test in which the TAS-102 preparation (tablet) is administered 1 time and 100mg/m for 1 day²(FTD equivalent), 5 days after 1 week administration and 2 days after discontinuation of the administration, 2 (33%) of 6 cases were effective (tumor was not deteriorated, and was stable). Experiment 2 was to dose the same formulation at 70mg/m for 1 day²(FTD equivalent) was administered in 3 divided doses for 5 days in 1 week, and was stopped for 2 days, and 4 (67%) of 6 cases were effective. That is, in 4 cases, tumor progression was arrested and no progression was observed, and in 1 case, tumor shrinkage was also observed. Thus, it was shown that the fractionated administration of TAS-102 is an effective method of administration for patients with cancer of the digestive organs who are not treated with the standard therapy or who are not treated with the standard therapy.

Example 2.

In the same manner as in example 1, clinical phase I test was performed on breast cancer patients.

Administering TAS-102 to a patient with breast cancer who has not been treated with standard therapy or has not been treated with standard therapy in an amount of 60mg/m in terms of FTD²Daily, 2 times oral administration (test 3) and 50mg/m²The therapeutic effect was examined in the case of oral administration 2 times a day (test 4).

The results are shown in FIG. 2. Test 3 TAS-102 formulation (tablet) at 60mg/m for 1 day²(FTD equivalent) was administered in 2 divided doses for 5 days in 1 week, and was stopped for 2 days, and 5 (71%) of 7 cases were effective. Experiment 4 was to dose the same formulation at 50mg/m for 1 day²(FTD equivalent) was administered in 2 divided doses for 5 days in 1 week, and was stopped for 2 days, and 7 (78%) of 9 cases were effective. That is, in almost all cases, tumor development stagnated and no exacerbations were found. Also, in many cases, SD lasts for half a yearIn the above 1 case, it was also found that SD lasted for more than one year. In the treatment of breast cancer, a treatment method which can be continued for more than 6 treatment courses (about half a year) is considered to be highly clinically practical. Thus, it was found that the fractionated administration of TAS-102 to a breast cancer patient who had failed the standard therapy or had no therapy was an effective administration method as in example 1.

Claims (15)

1. A therapeutic agent for cancer, characterized by:

the composition contains alpha, alpha-trifluorothymidine FTD and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride in a molar ratio of 1: 0.5, and the conversion amount of the FTD for therapeutic use is 20-80 mg/m²The dose per day is administered orally 2 to 4 times per day in 1 day.

2.The therapeutic agent for cancer according to claim 1, wherein:

conversion of quantities by FTDIs 25 to 75mg/m²The dose per day is administered orally in 2 or 3 divided doses per day.

3.The therapeutic agent for cancer according to claim 1, wherein:

the 1 week dosing schedule was: the medicine is administered 2 or 3 times in 1 day, 1 week for 5 days, and stopped taking 2 days.

4.The therapeutic agent for cancer according to claim 1, wherein:

the administration scheme is as follows: divided into 2 or 3 times for 1 day, 1 week for 5 days, and 2 days, 2 weeks for 2 weeks.

5.The therapeutic agent for cancer according to claim 1, wherein:

the dosage is 50-70 mg/m converted into FTD²Day/day.

6. The composition containing alpha, alpha-trifluorothymidine FTD and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride in a molar ratio of 1: 0.5 is prepared in an amount of 20 to 80mg/m in terms of FTD²The dose per day is 1 day, 2-4 times, and is used in a cancer therapeutic agent for oral administration.

7. Use according to claim 6, characterized in that:

the conversion amount of FTD is 25-75 mg/m²The dose per day is administered orally in 2 or 3 divided doses per day.

8. Use according to claim 6, characterized in that:

the 1 week dosing schedule was: the medicine is administered 2 or 3 times in 1 day, 1 week for 5 days, and stopped taking 2 days.

9. Use according to claim 6, characterized in that:

the administration scheme is as follows: divided into 2 or 3 times for 1 day, 1 week for 5 days, and 2 days, 2 weeks for 2 weeks.

10. Use according to claim 6, characterized in that:

the dosage is 50-70 mg/m converted into FTD²Day/day.

11. A method of treating cancer, comprising:

the composition containing alpha, alpha-trifluorothymidine FTD and 5-chloro-6- (1- (2-iminopyrrolidinyl) methyl) uracil hydrochloride in a molar ratio of 1: 0.5 is converted into 20-80 mg/m²The dose per day is administered orally 2 to 4 times per day in 1 day.

12. The treatment of claim 11 wherein:

the conversion amount of FTD is 25-75 mg/m²The dose per day is administered orally in 2 or 3 divided doses per day.

13. The treatment of claim 11 wherein:

the 1 week dosing schedule was: the medicine is administered 2 or 3 times in 1 day, 1 week for 5 days, and stopped taking 2 days.

14. The treatment of claim 11 wherein:

the administration scheme is as follows: divided into 2 or 3 times for 1 day, 1 week for 5 days, and 2 days, 2 weeks for 2 weeks.

15. The treatment of claim 11 wherein:

the dosage is 50-70 mg/m converted into FTD²Day/day.